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Background: The WHO grade of meningioma was updated in 2021 to include homozygous deletions of CDKN2A/B and TERT promotor mutations. Previous work including the recent cIMPACT-NOW statement have discussed the potential value of including chromosomal copy number alterations to help refine the current grading system. Methods: Chromosomal copy number profiles were inferred from from 1964 meningiomas using DNA methylation. Regularized Cox regresssion was used to identify CNAs independenly associated with post-surgical and post-RT PFS. Outcomes were stratified by WHO grade and novel CNAs to assess their potential value in WHO critiera. Results: Patients with WHO grade 1 tumours and chromosome 1p loss had similar outcomes to those with WHO grade 2 tumours (median PFS 5.83 [95% CI 4.36-Inf] vs 4.48 [4.09-5.18] years). Those with chromosome 1p loss and 1q gain had similar outcomes to those with WHO grade 3 cases regardless of initial grade (median PFS 2.23 [1.28-Inf] years WHO grade 1, 1.90 [1.23-2.25] years WHO grade 2, compared to 2.27 [1.68-3.05] years in WHO grade 3 cases overall). Conclusions: We advocate for chromosome 1p loss being added as a criterion for a CNS WHO grade of 2 meningioma and addition of 1q gain as a criterion for a CNS WHO grade of 3.
Background: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation model compatible with newer methylation arrays. Methods: The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. A nomogram was generated by incorporating our methylation predictor with WHO grade and extent of resection. Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and a retrospective cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperformed 2021 WHO grade in predicting postoperative recurrence. Dichotomizing into grade-specific risk subgroups was predictive of outcome within both WHO grades 1 and 2 tumours (log-rank p<0.05). Multivariable Cox regression demonstrated benefit of adjuvant radiotherapy in high-risk cases specifically, reinforcing its informative role in clinical decision making. Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms 2021 WHO grading in predicting time to recurrence. This will help improve prognostication and inform patient selection for RT.
Background: Meningiomas exhibit considerable heterogeneity. We previously identified four distinct molecular groups (immunogenic, NF2-wildtype, hypermetabolic, proliferative) which address much of this heterogeneity. Despite their utility, the stochasticity of clustering methods and the requirement of multi-omics data limits the potential for classifying cases in the clinical setting. Methods: Using an international cohort of 1698 meningiomas, we constructed and validated a machine learning-based molecular classifier using DNA methylation alone. Original and newly-predicted molecular groups were compared using DNA methylation, RNA sequencing, whole exome sequencing, and clinical outcomes. Results: Group-specific outcomes in the validation cohort were nearly identical to those originally described, with median PFS of 7.4 (4.9-Inf) years in hypermetabolic tumors and 2.5 (2.3-5.3) years in proliferative tumors (not reached in the other groups). Predicted NF2-wildtype cases had no NF2 mutations, and 51.4% had others mutations previously described in this group. RNA pathway analysis revealed upregulation of immune-related pathways in the immunogenic group, metabolic pathways in the hypermetabolic group and cell-cycle programs in the proliferative group. Bulk deconvolution similarly revealed enrichment of macrophages in immunogenic tumours and neoplastic cells in hypermetabolic/proliferative tumours. Conclusions: Our DNA methylation-based classifier faithfully recapitulates the biology and outcomes of the original molecular groups allowing for their widespread clinical implementation.
Background: The combination of PARP inhibitor and immune checkpoint inhibitors have been proposed as a potentially synergistic combinatorial treatment in IDH mutant glioma, targeting dysregulated homologous recombination repair pathways. This study analyzed the cell-free DNA methylome of patients in a phase 2 trial using the PARP inhibitor Olaparib and the PD-1 inhibitor Durvalumab. Methods: Patients with recurrent high-grade IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Serum was collected at baseline and monthly and cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. Binomial GLMnet models were developed and model performance was assessed using validation set data. Results: 29 patients were enrolled between 2020–2023. Patients received olaparib 300mg twice daily and durvalumab 1500mg IV every 4 weeks. The overall response rate was 10% via RANO criteria. 144 plasma samples were profiled with cfMeDIP-seq along with 30 healthy controls. The enriched circulating tumour DNA methylome during response periods exhibited a highly specific signature, accurately discriminating response versus failure (AUC 0.98 ± 0.03). Additionally, samples that were taken while on treatment were able to be discriminated from samples off therapy (AUC 0.74 ± 0.11). Conclusions: The cell-free plasma DNA methylome exhibits highly specific signatures that enable accurate prediction of response to therapy.
Despite advances in antiretroviral treatment (ART), human immunodeficiency virus (HIV) can detrimentally affect everyday functioning. Neurocognitive impairment (NCI) and current depression are common in people with HIV (PWH) and can contribute to poor functional outcomes, but potential synergies between the two conditions are less understood. Thus, the present study aimed to compare the independent and combined effects of NCI and depression on everyday functioning in PWH. We predicted worse functional outcomes with comorbid NCI and depression than either condition alone.
Methods:
PWH enrolled at the UCSD HIV Neurobehavioral Research Program were assessed for neuropsychological performance, depression severity (≤minimal, mild, moderate, or severe; Beck Depression Inventory-II), and self-reported everyday functioning.
Results:
Participants were 1,973 PWH (79% male; 66% racial/ethnic minority; Age: M = 48.6; Education: M = 13.0, 66% AIDS; 82% on ART; 42% with NCI; 35% BDI>13). ANCOVA models found effects of NCI and depression symptom severity on all functional outcomes (ps < .0001). With NCI and depression severity included in the same model, both remained significant (ps < .0001), although the effects of each were attenuated, and yielded better model fit parameters (i.e., lower AIC values) than models with only NCI or only depression.
Conclusions:
Consistent with prior literature, NCI and depression had independent effects on everyday functioning in PWH. There was also evidence for combined effects of NCI and depression, such that their comorbidity had a greater impact on functioning than either alone. Our results have implications for informing future interventions to target common, comorbid NCI and depressed mood in PWH and thus reduce HIV-related health disparities.
We present the first results from a new backend on the Australian Square Kilometre Array Pathfinder, the Commensal Realtime ASKAP Fast Transient COherent (CRACO) upgrade. CRACO records millisecond time resolution visibility data, and searches for dispersed fast transient signals including fast radio bursts (FRB), pulsars, and ultra-long period objects (ULPO). With the visibility data, CRACO can localise the transient events to arcsecond-level precision after the detection. Here, we describe the CRACO system and report the result from a sky survey carried out by CRACO at 110-ms resolution during its commissioning phase. During the survey, CRACO detected two FRBs (including one discovered solely with CRACO, FRB 20231027A), reported more precise localisations for four pulsars, discovered two new RRATs, and detected one known ULPO, GPM J1839 $-$10, through its sub-pulse structure. We present a sensitivity calibration of CRACO, finding that it achieves the expected sensitivity of 11.6 Jy ms to bursts of 110 ms duration or less. CRACO is currently running at a 13.8 ms time resolution and aims at a 1.7 ms time resolution before the end of 2024. The planned CRACO has an expected sensitivity of 1.5 Jy ms to bursts of 1.7 ms duration or less and can detect $10\times$ more FRBs than the current CRAFT incoherent sum system (i.e. 0.5 $-$2 localised FRBs per day), enabling us to better constrain the models for FRBs and use them as cosmological probes.
While there is a recognised role of optimising lifestyle behaviours such as diet and physical activity in the management of infertility, the best practice for lifestyle management of infertility remains unknown, and factors influencing the lifestyle behaviours of people with infertility are not well understood. The aim of this systematic review is to evaluate the barriers and enablers to a healthy lifestyle in people with infertility, from the perspectives of people with infertility and health professionals, in order to inform optimal behavioural change strategies for lifestyle management of infertility. Ovid MEDLINE(R), PsycINFO, EMBASE, EBM Reviews, and CINAHL Plus were searched from inception to 12th September 2022. Eligible studies were qualitative, quantitative or mixed-methods primary studies which explored barriers and/or enablers to lifestyle for infertility management, from the perspectives of people with infertility and/or health professionals. Two independent reviewers performed quality assessment, using the Centre for Evidence-Based Management Critical Appraisal of a Survey Tool (quantitative and mixed-methods studies) and the Critical Appraisal Skills Programme Qualitative Checklist (qualitative and mixed-methods studies). Data were analysed by inductive thematic analysis with themes mapped to the Capability, Opportunity, Motivation and Behaviour (COM-B) model(1) and Theoretical Domains Framework (TDF)(2). Relevant behaviour change techniques (BCTs)(3) to target the identified enablers and barriers were suggested. After screening 10703 citations and 82 full-texts, 22 studies were included (12 quantitative, 7 mixed-methods and 3 qualitative) with 18 studies including women with infertility (n = 2442), 10 including men with infertility (n = 1372) and 6 including health professionals (n = 261). From the perspectives of people with infertility, themes related to capability (e.g. strategies for behaviour change), opportunity (e.g. limited time, resources and money) and motivation (e.g. interplay between lifestyle and emotional state); themes mapped to 8 TDF domains. From the perspectives of health professionals, themes related to capability (e.g. identification of patients appropriate for lifestyle intervention), opportunity (e.g. mode of delivery) and motivation (e.g. professional responsibility); themes mapped to 6 TDF domains. 34 BCTs were identified across the suggested interventions. This systematic review found that several interacting factors influence lifestyle in people with infertility as well as health professional behaviour with regards to provision of lifestyle interventions for infertility. These factors can be targeted for optimisation of interventions. In light of the limited number of qualitative studies, there is a need for more qualitative research to gain deeper insights into the perspectives of people with infertility and health professionals for further exploration of the complex and interacting factors which shape lifestyle during the fertility journey.
Grain-cooking traditions in Neolithic China have been characterised as a ‘wet’ cuisine based on the boiling and steaming of sticky varieties of cereal. One of these, broomcorn millet, was one of the earliest Chinese crops to move westward into Central Asia and beyond, into regions where grains were typically prepared by grinding and baking. Here, the authors present the genotypes and reconstructed phenotypes of 13 desiccated broomcorn millet samples from Xinjiang (1700 BC–AD 700). The absence in this area of sticky-starch millet and vessels for boiling and steaming suggests that, as they moved west, East Asian cereal crops were decoupled from traditional cooking practices and were incorporated into local cuisines.
The focus on social determinants of health (SDOH) and their impact on health outcomes is evident in U.S. federal actions by Centers for Medicare & Medicaid Services and Office of National Coordinator for Health Information Technology. The disproportionate impact of COVID-19 on minorities and communities of color heightened awareness of health inequities and the need for more robust SDOH data collection. Four Clinical and Translational Science Award (CTSA) hubs comprising the Texas Regional CTSA Consortium (TRCC) undertook an inventory to understand what contextual-level SDOH datasets are offered centrally and which individual-level SDOH are collected in structured fields in each electronic health record (EHR) system potentially for all patients.
Methods:
Hub teams identified American Community Survey (ACS) datasets available via their enterprise data warehouses for research. Each hub’s EHR analyst team identified structured fields available in their EHR for SDOH using a collection instrument based on a 2021 PCORnet survey and conducted an SDOH field completion rate analysis.
Results:
One hub offered ACS datasets centrally. All hubs collected eleven SDOH elements in structured EHR fields. Two collected Homeless and Veteran statuses. Completeness at four hubs was 80%–98%: Ethnicity, Race; < 10%: Education, Financial Strain, Food Insecurity, Housing Security/Stability, Interpersonal Violence, Social Isolation, Stress, Transportation.
Conclusion:
Completeness levels for SDOH data in EHR at TRCC hubs varied and were low for most measures. Multiple system-level discussions may be necessary to increase standardized SDOH EHR-based data collection and harmonization to drive effective value-based care, health disparities research, translational interventions, and evidence-based policy.
Compared to older men, Alzheimer’s Disease (AD) is more common in older women, who present with higher levels of pathological tau and accelerated memory decline, although it is unclear why. Furthermore, sleep complaints increase with age, with older women reporting worse sleep quality than older men, and past studies have linked sleep disturbances to tau. Because of the life-long “verbal memory advantage” in women over men, nonverbal memory may more accurately reflect tau burden in women since sex differences are not as apparent. Here, in a sample of older women in the Women Inflammation Tau Study (WITS), we examined the associations between subjective sleep quality, tau in temporal regions, and memory, and whether tau would be more strongly related to nonverbal memory than verbal memory.
Participants and Methods:
In WITS, women have elevated AD polygenic hazard scores and have mild cognitive impairment as indicated by the telephone Montreal Cognitive Assessment (range:13-20). This preliminary sample of 20 women (aged 72.0±3.7) completed the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality in 7 domains of sleep health over the past month. A global score (range:0-21) is calculated, with a score >5 indicative of being a poor sleeper. Participants also underwent positron emission tomography (PET) with the 18F-MK6240 tracer and T1-weighted magnetic resonance imagining (MRI) to determine tau deposition. Standardized uptake value ratio (SUVR) was calculated using the inferior cerebellum grey matter as the reference region, which was created from Automated Anatomic Labeling atlas in native T1 space. The region of interest (ROI) was a composite meta-temporal region. The Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) Story A and B were administered to assess verbal memory. The Brief Visuospatial Memory Test-Revised (BVMT-R) was administered to assess nonverbal memory. Analysis focused on the delayed recall scores from the memory tests. Partial correlation was used to analyze the associations between PSQI global score, tau-PET SUVR in meta-temporal ROI, and memory delayed recall scores, while adjusting for age and education years.
Results:
8 women were poor sleepers indicated by the PSQI global score (mean:4.9±2). Worse subjective sleep quality was associated with greater tau in meta-temporal ROI (r=0.63, p=0.005) and lower BVMT-R delayed recall (r=-0.46, p=0.05). Sleep quality was not significantly related to either RAVLT or LM delayed recall (all p’s>0.40). Tau in meta-temporal ROI was not significantly associated with nonverbal (p=0.23) or verbal memory (all p’s>0.40) delayed recall.
Conclusions:
In this preliminary analysis, subjective sleep quality was linked to temporal tau deposition and nonverbal memory delayed recall, which may suggest that poor sleep exacerbates pathogenesis of tau that leads to memory difficulties in older women at increased risk for AD. Although tau was not significantly related to any memory measures, we will explore whether tau will mediate or moderate the relationship between sleep quality and nonverbal memory once we are powered to do so. Continual evaluation and treatment of sleep may be imperative in mitigating AD risk, especially for older women, however, future longitudinal studies will be necessary to investigate this.
The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion and probed whether varying levels of plasma Alzheimer’s disease (AD) biomarkers (Aß42/40 ratio and ptau181) moderated these relationships.
Participants and Methods:
64 dementia-free community-dwelling older adults (ages 55-87) recruited across two studies underwent structural and functional neuroimaging on the same MRI scanner. 3D-pCASL MRI measured regional cerebral blood flow in limbic and frontal cortical regions, while T1-FSE MRI quantified rostral LC-MRI contrast, a well-established proxy measure of LC structural integrity. A subset of participants underwent fasting blood draw to measure plasma AD biomarker concentrations (Aß42/40 ratio and ptau181). Multiple linear regression models examined associations between perfusion and LC integrity, with rostral LC-MRI contrast as predictor, regional CBF as outcome, and age and study as covariates. Moderation analyses included additional terms for plasma AD biomarker concentration and plasma x LC interaction.
Results:
Greater rostral LC-MRI contrast was linked to lower regional perfusion in limbic regions, such as the amygdala (ß = -0.25, p = 0.049) and entorhinal cortex (ß = -0.20, p = 0.042), but was linked to higher regional perfusion in frontal cortical regions, such as the lateral (ß = 0.28, p = 0.003) and medial (ß = 0.24, p = 0.05) orbitofrontal (OFC) cortices. Plasma amyloid levels moderated the relationship between rostral LC and amygdala CBF (Aß42/40 ratio x rostral LC interaction term ß = -0.31, p = 0.021), such that as plasma Aß42/40 ratio decreased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and amygdala perfusion decreased. Plasma ptau181levels moderated the relationship between rostral LC and entorhinal CBF (ptau181 x rostral LC interaction term ß = 0.64, p = 0.001), such that as ptau181 increased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and entorhinal perfusion decreased. For frontal cortical regions, ptau181 levels moderated the relationship between rostral LC and lateral OFC perfusion (ptau181 x rostral LC interaction term ß = -0.54, p = .004), as well as between rostral LC and medial OFC perfusion (ptau181 x rostral LC interaction term ß = -0.53, p = .005), such that as ptau181 increased (i.e., greater pathology), the strength of the positive relationship between rostral LC integrity and frontal perfusion decreased.
Conclusions:
LC integrity is linked to regional cortical perfusion in non-demented older adults, and these relationships are moderated by plasma AD biomarker concentrations. Variable directionality of the associations between the LC and frontal versus limbic perfusion, as well as the differential moderating effects of plasma AD biomarkers, may signify a compensatory mechanism and a shifting pattern of hyperemia in the presence of aggregating AD pathology. Linking LC integrity and cerebrovascular regulation may represent an important understudied pathway of dementia risk and may help to bridge competing theories of dementia progression in preclinical AD studies.
Innovations in horse equipment during the early Middle Ages provided advantages to societies from the steppes, reshaping the social landscape of Eurasia. Comparatively little is known about the precise origin of these crucial advances, although the available evidence points to early adoption in East Asia. The authors present new archaeological discoveries from western and northern Mongolia, dating to the fourth and fifth centuries AD, including a wooden frame saddle with horse hide components from Urd Ulaan Uneet and an iron stirrup from Khukh Nuur. Together, these finds suggest that Mongolian groups were early adopters of stirrups and saddles, facilitating the expansion of nomadic hegemony across Eurasia and shaping the conduct of medieval mounted warfare.
Despite the importance of timing of nerve surgery after peripheral nerve injury, optimal timing of intervention has not been clearly delineated. The goal of this study is to explore factors that may have a significant impact on clinical outcomes of severe peripheral nerve injury that requires reconstruction with nerve transfer or graft.
Materials and Methods:
Adult patients who underwent peripheral nerve transfer or grafting in Alberta were reviewed. Clustered multivariable logistic regression analysis was used to examine the association of time to surgery, type of nerve repair, and patient characteristics on strength outcomes. Cox proportional hazard regression analysis model was used to examine factors correlated with increased time to surgery.
Results:
Of the 163 patients identified, the median time to surgery was 212 days. For every week of delay, the adjusted odds of achieving Medical Research Council strength grade ≥ 3 decreases by 3%. An increase in preinjury comorbidities was associated with longer overall time to surgery (aHR 0.84, 95% CI 0.74–0.95). Referrals made by surgeons were associated with a shorter time to surgery compared to general practitioners (aHR 1.87, 95% CI 1.14–3.06). In patients treated with nerve transfer, the adjusted odds of achieving antigravity strength was 388% compared to nerve grafting; while the adjusted odds decreased by 65% if the injury sustained had a pre-ganglionic injury component.
Conclusion:
Mitigating delays in surgical intervention is crucial to optimizing outcomes. The nature of initial nerve injury and surgical reconstructive techniques are additional important factors that impact postoperative outcomes.
In a recent survey of nematodes associated with tobacco in Shandong, China, the root-lesion nematode Pratylenchus coffeae was identified using a combination of morphology and molecular techniques. This nematode species is a serious parasite that damages a variety of plant species. The model plant benthi, Nicotiana benthamiana, is frequently used to study plant-disease interactions. However, it is not known whether this plant species is a host of P. coffeae. The objectives of this study were to evaluate the parasitism and pathogenicity of five populations of the root-lesion nematode P. coffeae on N. benthamiana.N. benthamiana seedlings with the same growth status were chosen and inoculated with 1,000 nematodes per pot. At 60 days after inoculation, the reproductive factors (Rf = final population densities (Pf)/initial population densities (Pi)) for P. coffeae in the rhizosphere of N. benthamiana were all more than 1, suggesting that N. benthamiana was a good host plant for P. coffeae.Nicotiana. benthamiana infected by P. coffeae showed weak growth, decreased tillering, high root reduction, and noticeable brown spots on the roots. Thus, we determined that the model plant N. benthamiana can be used to study plant-P. coffeae interactions.
In recent years, there has been significant momentum in applying deep learning (DL) to machine health monitoring (MHM). It has been widely claimed that DL methodologies are superior to more traditional techniques in this area. This paper aims to investigate this claim by analysing a real-world dataset of helicopter sensor faults provided by Airbus. Specifically, we will address the problem of machine sensor health unsupervised classification. In a 2019 worldwide competition hosted by Airbus, Fujitsu Systems Europe (FSE) won first prize by achieving an F1-score of 93% using a DL model based on generative adversarial networks (GAN). In another comprehensive study, various modified and existing image encoding methods were compared for the convolutional auto-encoder (CAE) model. The best classification result was achieved using the scalogram as the image encoding method, with an F1-score of 91%. In this paper, we use these two studies as benchmarks to compare with basic statistical analysis methods and the one-class supporting vector machine (SVM). Our comparative study demonstrates that while DL-based techniques have great potential, they are not always superior to traditional methods. We therefore recommend that all future published studies of applying DL methods to MHM include appropriately selected traditional reference methods, wherever possible.
TDuring COVID-19 pandemic, it was noticed that it was students who were mostly affected by the changes that aroused because of the pandemic. The interesting part is whether students’ well-being could be associated with their fields of study as well as coping strategies.
Objectives
In this study, we aimed to assess 1) the mental health of students from nine countries with a particular focus on depression, anxiety, and stress levels and their fields of study, 2) the major coping strategies of students after one year of the COVID-19 pandemic.
Methods
We conducted an anonymous online cross-sectional survey on 12th April – 1st June 2021 that was distributed among the students from Poland, Mexico, Egypt, India, Pakistan, China, Vietnam, Philippines, and Bangladesh. To measure the emotional distress, we used the Depression, Anxiety, and Stress Scale-21 (DASS-21), and to identify the major coping strategies of students - the Brief-COPE.
Results
We gathered 7219 responses from students studying five major studies: medical studies (N=2821), social sciences (N=1471), technical sciences (N=891), artistic/humanistic studies (N=1094), sciences (N=942). The greatest intensity of depression (M=18.29±13.83; moderate intensity), anxiety (M=13.13±11.37; moderate intensity ), and stress (M=17.86±12.94; mild intensity) was observed among sciences students. Medical students presented the lowest intensity of all three components - depression (M=13.31±12.45; mild intensity), anxiety (M=10.37±10.57; moderate intensity), and stress (M=13.65±11.94; mild intensity). Students of all fields primarily used acceptance and self-distraction as their coping mechanisms, while the least commonly used were self-blame, denial, and substance use. The group of coping mechanisms the most frequently used was ‘emotional focus’. Medical students statistically less often used avoidant coping strategies compared to other fields of study. Substance use was only one coping mechanism that did not statistically differ between students of different fields of study. Behavioral disengagement presented the highest correlation with depression (r=0.54), anxiety (r=0.48), and stress (r=0.47) while religion presented the lowest positive correlation with depression (r=0.07), anxiety (r=0.14), and stress (r=0.11).
Conclusions
1) The greatest intensity of depression, anxiety, and stress was observed among sciences students, while the lowest intensity of those components was found among students studying medicine.
2) Not using avoidant coping strategies might be associated with lower intensity of all DASS components among students.
3) Behavioral disengagement might be strongly associated with greater intensity of depression, anxiety, and stress among students.
4) There was no coping mechanism that provided the alleviation of emotional distress in all the fields of studies of students.
Despite replicated cross-sectional evidence of aberrant levels of peripheral inflammatory markers in individuals with major depressive disorder (MDD), there is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies.
Objectives
To assess associations between plasma levels of pro-inflammatory markers and treatment response to escitalopram and adjunctive aripiprazole in adults with MDD.
Methods
In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10– 20 mg daily for 8 weeks. Responders continued on escitalopram while non-responders received adjunctive aripiprazole 2–10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers – C-reactive protein, Interleukin (IL)-1β, IL-6, IL-17, Interferon gamma (IFN)-Γ, Tumour Necrosis Factor (TNF)-α, and Chemokine C–C motif ligand-2 (CCL-2) - measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyses to assess associations between inflammatory markers and treatment response.
Results
Pre-treatment levels of IFN-Γ and CCL-2 were significantly higher in escitalopram non-responders compared to responders. Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16.
Conclusions
Pre-treatment levels of IFN-Γ and CCL-2 were predictive of response to escitalopram. Increasing levels of these pro-inflammatory markers may predict non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.
Major Depressive Disorder (MDD) is one of the most common mental illnesses worldwide and is strongly associated with suicidality. Commonly used treatments for MDD with suicidality include crisis intervention, oral antidepressants (although risk of suicidal behavior is high among non-responders and during the first 10-14 days of the treatment) benzodiazepines and lithium. Although several interventions addressing suicidality exist, only few studies have characterized in detail patients with MDD and suicidality, including treatment, clinical course and outcomes. Patient Characteristics, Validity of Clinical Diagnoses and Outcomes Associated with Suicidality in Inpatients with Symptoms of Depression (OASIS-D)-study is an investigator-initiated trial funded by Janssen-Cilag GmbH.
Objectives
For population 1 out of 3 OASIS-D populations, to assess the sub-population of patients with suicidality and its correlates in hospitalized individuals with MDD.
Methods
The ongoing OASIS-D study consecutively examines hospitalized patients at 8 German psychiatric university hospitals treated as part of routine clinical care. A sub-group of patients with persistent suicidality after >48 hours post-hospitalization are assessed in detail and a sub-group of those are followed for 6 months to assess course and treatment of suicidality associated with MDD. The present analysis focuses on a preplanned interim analysis of the overall hospitalized population with MDD.
Results
Of 2,049 inpatients (age=42.5±15.9 years, females=53.2%), 68.0% had severe MDD without psychosis and 21.2% had moderately severe MDD, with 16.7% having treatment-resistant MDD. Most inpatients referred themselves (49.4%), followed by referrals by outpatient care providers (14.6%), inpatient care providers (9.0%), family/friends (8.5%), and ambulance (6.8%). Of these admissions, 43.1% represented a psychiatric emergency, with suicidality being the reason in 35.9%. Altogether, 72.4% had at least current passive suicidal ideation (SI, lifetime=87.2%), including passive SI (25.1%), active SI without plan (15.5%), active SI with plan (14.2%), and active SI with plan+intent (14.1%), while 11.5% had attempted suicide ≤2 weeks before admission (lifetime=28.7%). Drug-induced mental and behavioral disorders (19.6%) were the most frequent comorbid disorders, followed by personality disorders (8.2%). Upon admission, 64.5% were receiving psychiatric medications, including antidepressants (46.7%), second-generation antipsychotics (23.0%), anxiolytics (11.4%) antiepileptics (6.0%), and lithium (2.8%). Altogether, 9.8% reported nonadherence to medications within 6 months of admission.
Conclusions
In adults admitted for MDD, suicidality was common, representing a psychiatric emergency in 35.9% of patients. Usual-care treatments and outcomes of suicidality in hospitalized adults with MDD require further study.