title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
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Main Outcomes and Measures | depressive symptoms | ADVERSE EFFECTS | The primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores). | PMC10167565 |
Results | Of 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Mei... | PMC10167565 | ||
Conclusions and Relevance | MDD, depressive | ADVERSE EFFECTS | In this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in ... | PMC10167565 |
Trial Registration | ClinicalTrials.gov Identifier: This randomized clinical trial examines whether tricyclic antidepressant (TCA) dosing based on pharmacogenetics according to the Dutch Pharmacogenetics Working Group guidelines results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment. | PMC10167565 | ||
Introduction | ADVERSE EFFECTS | Pharmacogenetics has the potential to personalize antidepressant treatment, yet implementation in psychiatry is still very limited.Antidepressants are metabolized by various isoforms of cytochrome P450 (CYP450) enzymes, notably the CYP450 2D6 (CYP2D6) and CYP450 2C19 (CYP2C19) isozymes.Currently, several guidelines are... | PMC10167565 | |
Methods | PMC10167565 | |||
Study Design | The Pharmacogenetics for Individualized Tricyclic Antidepressant (PITA) dosing study was a multicenter RCT in which patients were enrolled between June 1, 2018, and January 1, 2022. The trial protocol is provided in The participating institutions were hospitals and mental health care institutions in the Netherlands (eT... | PMC10167565 | ||
Flowchart of the PITA (Pharmacogenetics for Individualized Tricyclic Antidepressant [TCA]) Study | The reference group consisted of nonrandomized patients with a cytochrome P450 2D6 isozyme (CYP2D6) normal metabolizer phenotype receiving usual treatment. PIT indicates pharmacogenetics-informed treatment; TAU, treatment as usual. | PMC10167565 | ||
Participants | unipolar nonpsychotic MDD | Patients were enrolled by their treating psychiatrist. They had a primary diagnosis of unipolar nonpsychotic MDD according to | PMC10167565 | |
Randomization | With the use of stratified block randomization, patients were randomized (1:1) to the PIT or control group by a staff member not involved in this study. The stratification was performed in the following order: (1) CYP2D6 metabolizer phenotype (and CYP2C19 metabolizer phenotype for those receiving imipramine), categoriz... | PMC10167565 | ||
Intervention | Patients randomized to the PIT group received an initial TCA dosage according to the DPWG guidelines (eTables 2 and 3 in | PMC10167565 | ||
Outcome Measures | depression, depressive symptoms | ADVERSE EFFECTS | The primary outcome was time (in days) to therapeutic TCA plasma concentrations. Secondary outcomes were severity of depressive symptoms and frequency and severity of adverse effects. Severity of depressive symptoms was measured weekly through the HAMD-17 (score range, 0-52, with higher scores indicating greater depres... | PMC10167565 |
Sample Size Calculation | SECONDARY | To our knowledge, no previous studies have assessed time to attainment of a therapeutic TCA plasma concentration by pharmacogenetics-informed dosing according to DPWG guidelines. We assumed that 50% of the control group would reach a therapeutic plasma concentration within 4 weeks and that 50% of the PIT group would re... | PMC10167565 | |
Statistical Analysis | depression | ADVERSE EFFECTS | All analyses were performed according to a modified intention-to-treat principle, meaning that patients were included if at least 1 TCA dose was administered. The primary analysis was presented in a Kaplan-Meier survival curve and conducted using a 2-sided log-rank test. In case no therapeutic plasma concentration was ... | PMC10167565 |
Results | PMC10167565 | |||
Baseline Characteristics | depression, depressive symptoms | Among 171 included patients, 125 patients (73.1%) were randomized to the PIT (n = 63) or control (n = 62) group. A total of 14 randomized patients (11.2%) were excluded from the analysis because TCA treatment was not initiated due to early improvement of depressive symptoms or violation of the study protocol (At baseli... | PMC10167565 | |
Baseline Characteristics of Patients | depression, Depression | Abbreviations: CYP2C19, cytochrome P450 2C19 isozyme; CYP2D6, cytochrome P450 2D6 isozyme; HAMD-17, 17-item Hamilton Rating Scale for Depression; IM, intermediate metabolizer; NM, normal metabolizer; PIT, pharmacogenetics-informed treatment; PM, poor metabolizer; TCA, tricyclic antidepressant; UM, ultrarapid metabolize... | PMC10167565 | |
Attainment of Therapeutic Plasma Concentrations | A total of 47 patients (83.9%) in the PIT group and 45 patients (81.8%) in the control group attained a therapeutic concentration. The PIT group reached therapeutic concentrations significantly faster than the control group (mean [SD], 17.3 [11.2] days vs 22.0 [10.2] days; Kaplan-Meier χ | PMC10167565 | ||
Survival Curves for Time to Therapeutic Plasma Concentrations of Tricyclic Antidepressants Overall | Vertical bars on survival curves represent times of censoring. PIT indicates pharmacogenetics-informed treatment; TAU, treatment as usual.Post hoc analyses demonstrated that the effect was mainly found for nortriptyline (χ | PMC10167565 | ||
Survival Curves for Time to Therapeutic Plasma Concentrations of Nortriptyline and Clomipramine | Vertical bars on survival curves represent times of censoring. PIT indicates pharmacogenetics-informed treatment; TAU, treatment as usual. | PMC10167565 | ||
Effects on Depressive Symptoms | depression | At baseline, depression severity (measured by HAMD-17 score) was similar between the PIT and control groups ( | PMC10167565 | |
Treatment Effectiveness and Severity of Adverse Effects | Depression, HAMD-17 | ADVERSE EFFECTS | Treatment effectiveness was measured by the 17-item Hamilton Rating Scale for Depression (HAMD-17), and severity of adverse effects was measured by item 2 of the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER). Whiskers represent SEs. PIT indicates pharmacogenetics-informed treatment; TAU, treatment as... | PMC10167565 |
Adverse Effects | ADVERSE EFFECTS, INTERACTIONS | The interaction between severity of adverse effects and time was significantly different between the PIT and control groups (Interactions between the frequency of adverse effects (FIBSER item 1) and time ( | PMC10167565 | |
Reference Group | In the reference group consisting of 46 nonrandomized patients with a CYP2D6 NM phenotype receiving usual treatment, 9 patients did not initiate TCAs; therefore, analyses were conducted for 37 patients. Baseline characteristics are shown in eTable 5 in | PMC10167565 | ||
Discussion | PMC10167565 | |||
Main Findings | depressive symptoms | ADVERSE EFFECTS, SECONDARY | In this first RCT to date comparing PIT with standard treatment, we found that PIT resulted in faster attainment of therapeutic TCA plasma concentrations without exposing patients to more severe adverse effects. Our analyses indicated a mean reduction of 5 days in time to attainment of therapeutic concentrations compar... | PMC10167565 |
Limitations | This study has several limitations. First, dosage adjustments based on therapeutic drug monitoring were performed weekly in both study groups; therefore, usual treatment was of higher quality than that found in standard clinical practice in which it takes several weeks until plasma concentrations are measured. | PMC10167565 | ||
Conclusions | MDD, depressive symptoms | This RCT found that application of the DPWG guidelines in TCA treatment of MDD could be safely applied and resulted in faster attainment of therapeutic plasma concentrations. No effect on depressive symptoms was found. The results of this study imply that the benefits of preemptive pharmacogenetic testing may vary betw... | PMC10167565 | |
Introduction | CORTEX | Neurofeedback (NF) is “a non-invasive brain stimulation technique equipped with a closed-loop control mechanism, whereby information on the dynamics, usually non-observable, is made observable to subjects, who can then use it to retroact on it, and push it towards functionally desirable goal states. NF involves definin... | PMC10035884 | |
Theta: A promising neural target for training executive control | Extensive research has shown that EEG-theta synchronization is central to executive control [In a meta-analytic review of the NF literature, Rogala et al. [As cited by Rogala et al. [More recently, Brandmeyer & Delorme [Wang & Hsieh [We are not aware of NF research designed to promote Overall, research on Fmθ NF traini... | PMC10035884 | ||
Unresolved issues and gaps | One issue of previous NF training studies which has not been fully addressed concerns the sham control. Sham control conditions have typically been implemented as various forms of false feedback (e.g., receiving feedback from another participant’s previous recordings) or random feedback from one’s own recordings (e.g.,... | PMC10035884 | ||
Current study | From a dynamical systems perspective, it is conceivable that designing NF to more flexibly train variable multistable states (e.g., transitioning between activation and inhibition) by rapidly alternating increasing and decreasing Fmθ feedback may lead to improved executive task performance relative to feedback designed... | PMC10035884 | ||
Materials and methods | PMC10035884 | |||
Participants | SESSION | Thirty (N = 30; 13 female) young healthy adults (ages 18–40 yr; mean 24.99 ±3.21) participated in seven separate sessions within a three-week interval: one Orientation Session, five combined NF training + Go-NoGo shooting (SH) task testing sessions, and one post-training SH task testing session. Electroencephalography ... | PMC10035884 | |
Study design and timeline | The participants were randomly assigned to either the INC or ALT group. Those in the INC group (n = 12; 5 female) were instructed to increase their Fmθ power during each of six trials in each of six blocks in each of five sessions. Those in the ALT group (n = 18; 8 female) were instructed to either increase or decrease... | PMC10035884 | ||
Task design. | Experiment design illustrating the Intake/Orientation session, five sessions of NF training and six sessions of Go-NoGo SH task testing. Insert above shows six blocks (6 trials/block) of NF training for the INC (all increase Fmθ) and ALT (3 increase and 3 decrease Fmθ randomly assigned) groups with eyes-open rest perio... | PMC10035884 | ||
Equipment and apparati | PMC10035884 | |||
Neurofeedback training and Go-NoGo shooting task | EVENT | An HTC Vive virtual reality system (The SH task paradigm was programmed to simulate a target range from a first-person (egocentric) perspective and transmitted the following event markers online in real-time from the scenario generation computer via parallel cable connection to the EEG recording system: (1) onset of ta... | PMC10035884 | |
Electroencephalography (EEG) recording | EEG data were acquired at 2048 Hz and referenced online to the Common Mode Sense (CMS) and Direct Right Leg (DRL) electrodes using a 64 (+8 external) channel BioSemi system (Amsterdam, The Netherlands; | PMC10035884 | ||
Data integration and synchronization | All data were integrated and synchronized using Lab Streaming Layer (LSL [ | PMC10035884 | ||
Procedures | PMC10035884 | |||
Intake/Orientation session | Anxiety | BLIND | Interested participants were first asked to come to the Virtual Reality Laboratory at the Technology Research Center (TRC) at UMBC for an Intake/Orientation meeting. During this session, the participants were provided a more thorough description of the study and further explanation of procedures and demands, shown brie... | PMC10035884 |
Familiarization and training procedure (FTP) | SESSION | To minimize novelty and learning effects during experimental testing, we first presented the participants a Familiarization and Training Procedure (FTP) during the Orientation Session. The FTP was conducted without physiological recordings or instrumentation beyond the Vive headset and hand controller, which was used i... | PMC10035884 | |
Individual performance thresholding procedure (IPTP) | To induce a task-relevant time-stress effect, while accounting for individual differences in the ability to perform the task, we determined each participant’s individual reaction time thresholds (i.e., individualized target exposure durations) corresponding to the 50th (High time stress) and 90th (Low time stress) perc... | PMC10035884 | ||
Compensation and scheduling | SESSION | We provided monetary compensation to attract willing participants, reduce attrition, and incentivize completion of all training and testing sessions. We paid $10/hr as base pay for participation in each session and an additional $100 bonus for completion of the entire study. We scheduled dates and times of the six rema... | PMC10035884 | |
Statistical analysis | Multilevel linear modeling (MLM) was applied to examine effects of NF training on Fmθ, and to examine training-related changes in Fmθ and behavioral performance measures during the Go-NoGo shooting task (% errors of commission, accuracy, RT). Models were constructed in four steps and participants were used as the level... | PMC10035884 | ||
Responder-only analyses | REGRESSION | Responder-only analyses were also conducted, which are reported in Supporting information. For the analyses, participants were considered responders if either session or moderation could predict their Fmθ power during NF training using univariate regression analyses. Using these criteria 18 participants were considered... | PMC10035884 | |
Results | PMC10035884 | |||
Neurofeedback training | An intercepts only model was conducted, Fmθ ( | PMC10035884 | ||
Fmθ changes within and across sessions for each group during NF. | SE | Changes in Fmθ over Blocks and Sessions of NF training for each Group (error bars are SE). | PMC10035884 | |
FCz full spectrum and topographic maps of theta and alpha power for the first and last training sessions for each group during NF. | SESSION | Topographic maps of mean theta (4–7 Hz; top row) and alpha (8–13 Hz; bottom row) averaged over Blocks for Session 1 (left map) and Session 5 (right map) of NF training and corresponding mean power spectra at FCz from 0–30 Hz for INC group (left spectra), ALT group, down-modulation (middle spectra), and ALT group, up-mo... | PMC10035884 | |
Full MLM of Fmθ during NF training. | PMC10035884 | |||
Go-NoGo shooting task | PMC10035884 | |||
Frontal theta | Fmθ from shooting task trials ( | PMC10035884 | ||
Fmθ changes across sessions in low and high time-stress conditions for each group during SH. | SE | Changes in Fmθ over Sessions during Go-NoGo shooting task in Low (left) and High (right) time-stress conditions for each Group (error bars are SE). | PMC10035884 | |
FCz full spectrum and topographic maps of theta and alpha power for the first and last testing sessions for each group during SH. | SESSION | Topographic maps of mean theta (4–7 Hz; top row) and alpha (8–13 Hz; bottom row) power averaged over Blocks for Session 1 (left map) and Session 6 (right map) during SH task and corresponding mean power spectra at FCz from 0–30 Hz for INC group (column 1) and ALT group (column 2) in Low (row 1) and High (row 2) time st... | PMC10035884 | |
Full MLMs of Fmθ during Go-NoGo shooting task. | PMC10035884 | |||
Behavioral performance | PMC10035884 | |||
% Errors of commission | Examining commission errors ( | PMC10035884 | ||
Changes in errors of commission across sessions in low and high time-stress conditions for each group. | SE | Percentage errors of commission over Sessions in the Low (left) and High (right) time-stress conditions for each Group (error bars are SE). | PMC10035884 | |
Full MLMs for behavioral measures from Go-NoGo shooting task. | PMC10035884 | |||
Accuracy | The intercepts only model for accuracy ( | PMC10035884 | ||
Changes in shooting accuracy across sessions in low and high time-stress conditions for each group. | SE | Percentage enemy targets hit over Sessions in the Low (left) and High (right) time-stress conditions for each Group (error bars are SE). | PMC10035884 | |
Reaction times | Reaction time ( | PMC10035884 | ||
Changes in RTs across sessions in low and high time-stress conditions for each group. | SE | RTs to enemy targets over Sessions in the Low (left) and High (right) time-stress conditions for each Group (error bars are SE). | PMC10035884 | |
Discussion | SAID | We investigated neurobehavioral effects of a novel NF training protocol that targeted both up- and down-modulation of Fmθ. This novel alternating up/down modulation condition (ALT) was compared to a more common NF training condition targeting solely up-modulation of Fmθ (INC). Accurate contingent feedback was provided ... | PMC10035884 | |
Neurofeedback training | SESSION | In an attempt to disentangle confounding effects of training-related increases in Fmθ observed in previous research in real NF versus sham control groups, i.e., self-regulation based on contingent feedback, or other mechanisms, we tested two competing hypotheses while holding accurate contingent feedback constant betwe... | PMC10035884 | |
Go-NoGo shooting task performance | Regarding training-related performance outcomes, we hypothesized that the ALT group would improve at a greater rate on the Go-NoGo shooting task over sessions, as the dynamics-to-function mapping of activation and inhibition attempted in training would be more specific to the demands of the Go-NoGo task to which the de... | PMC10035884 | ||
Limitations and future directions | fatigue | A major limitation of this study was that we did not include a third sham control group, and/or a down-regulation only NF training group. This was mainly because of practical concerns of time (for both experimenters and participants) and cost. Ideally, we would have included a sham control group and an exclusive down-m... | PMC10035884 | |
Summary and conclusions | In the present study, the difference between ALT and INC training groups was task-switching of top-down goals of increasing or alternating increasing and decreasing Fmθ activity. Considering that accurate contingent feedback was provided in both groups, coupling between top-down goals and bottom-up error-related proces... | PMC10035884 | ||
Supporting information | PMC10035884 | |||
Responder-only changes in Fmθ over sessions during NF training and Go-NoGo shooting task and changes in errors of commission, accuracy, and RT over sessions during Go-NoGo shooting task. | (DOCX)Click here for additional data file. | PMC10035884 | ||
Full MLM for responder-only of Fmθ during NF training and Go-NoGo shooting task and errors of commission, accuracy, and RT over sessions during Go-NoGo shooting task. | (DOCX)Click here for additional data file. | PMC10035884 | ||
Results of responder-only MLM analyses of Fmθ during NF training and Go-NoGo shooting task and errors of commission, accuracy, and RT over sessions during Go-NoGo shooting task. | (DOCX)Click here for additional data file.We gratefully acknowledge Michael Hammond, Zheng Li, and Vikramaditya Battina for engineering system design and testing, and Theo Feng for scheduling, data collection, and study administration. We also thank the peer reviewers for their valuable contribution to this manuscript. | PMC10035884 | ||
Background | critically ill obese, non-obese, ARDS | OBESE, ARDS | Respiratory mechanics is a key element to monitor mechanically ventilated patients and guide ventilator settings. Besides the usual basic assessments, some more complex explorations may allow to better characterize patients’ respiratory mechanics and individualize ventilation strategies. These advanced respiratory mech... | PMC10476380 |
Methods | All intubated patients admitted in two ICUs for any cause were prospectively included. Gas exchange and respiratory mechanics including esophageal pressure and end-expiratory lung volume (EELV) measurements and low-flow insufflation to detect complete airway closure were assessed in standardized conditions (tidal volum... | PMC10476380 | ||
Results | non-obese, ARDS | OBESE, ARDS | Among the 149 analyzed patients, 52 (34.9%) were obese and 90 (60.4%) had ARDS (65.4% and 57.8% of obese and non-obese patients, respectively, | PMC10476380 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s13054-023-04623-2. | PMC10476380 | ||
Keywords | PMC10476380 | |||
Introduction | Respiratory mechanics is a key element in clinical practice to monitor mechanically ventilated patients and guide ventilator settings [ | PMC10476380 | ||
Patients and methods | PMC10476380 | |||
Patients’ selection | cardiac arrest | CARDIAC ARREST, PNEUMOTHORAX | All patients admitted from March 2018 to January 2020 in two academic hospital ICUs (Angers and Strasbourg, France) intubated and mechanically ventilated for any cause were prospectively included in the study within 24 h after intubation. Exclusion criteria were age < 18 years, pneumothorax, contraindication to esophag... | PMC10476380 |
Study protocol | PMC10476380 | |||
Settings | HEMODYNAMIC INSTABILITY, RECRUITMENT | All patients received deep sedation and neuromuscular blockers at the time of measurements and were ventilated using an EngströmEsophageal pressure was measured with a specific nasogastric feeding tube equipped with an esophageal balloon (NutriventTo normalize volume history, a recruitment maneuver was performed in vol... | PMC10476380 | |
Measurements | expiratory occlusion | BLIND | All esophageal pressure signal recordings were independently inspected by two investigators blind to the other clinical data, and those considered non-valid were excluded from the analyses including esophageal pressure data.Inspiratory and expiratory occlusion maneuvers were performed to measure Abdominal pressure (An ... | PMC10476380 |
Calculated variables | DPThe difference between P1 and Inspiratory (The lung driving pressure (DPThe elastance ratio (As DPThe ratios Dead space was assessed using ventilatory ratio, which was computed as minute ventilation (mL/min) × PaCO | PMC10476380 | ||
Other collected data | ARDS | OPACITIES, ARDS, BLIND, CHRONIC RESPIRATORY DISEASE | Age, height, weight, past medical history of chronic respiratory disease, immunodepression, Sequential Organ Failure Assessment (SOFA) score [The lung opacities were independently assessed on chest X-rays by two experienced investigators blind to clinical data.The diagnosis of ARDS was performed using the criteria of t... | PMC10476380 |
Statistical analysis | obesity | OBESITY | Results are presented as median [interquartile range] and number (percentage). Normality of the variables was assessed using the D’Agostino & Pearson test. The study population was divided into four groups according to the presence of obesity or not (BMI < or ≥ 30 kg m | PMC10476380 |
Results | PMC10476380 | |||
Main patients’ characteristics | non-obese, ARDS | ACUTE RESPIRATORY DISTRESS SYNDROME, OBESE, ARDS | One hundred and sixty-four patients were included in the study. One hundred and forty-nine of them were included in the analysis (15 patients were excluded because of lack of data due to technical issues in recordings or major deviations in study protocol). Valid esophageal pressure measurements were analyzed in 124 pa... | PMC10476380 |
Gas exchange | obesity, ARDS | OBESITY, ARDS | Gas exchange in the patients categorized according to the presence or not of obesity and/or ARDS is presented in Table Gas exchange and respiratory mechanicsData are presented as median [interquartile range] or number (percentage)RR, Respiratory Rate; VE, Minute ventilation; FiO* | PMC10476380 |
Airway closure and driving pressure | A complete airway closure assessed with a PEEP of 5 cmHDPΔP1- | PMC10476380 | ||
Lung driving pressure, plateau pressure of the lung and lung stress | DP | PMC10476380 | ||
Conclusion | obese, critically ill, non-obese ARDS, ARDS | OBESE, CRITICALLY ILL, ARDS | Basic respiratory mechanics and gas exchange features of obese patients are similar to those observed in non-obese ARDS patients. But an advanced assessment of respiratory mechanics allows to show that end-expiratory esophageal pressure, although largely distributed, is higher in obese patients. Chest wall compliance i... | PMC10476380 |
Acknowledgements | The authors would like to greatly acknowledge all the medical and non‐medical teams of the Angers and Strasbourg Medical ICUs. | PMC10476380 | ||
Author contributions | FM | FB, JCR, and AM designed the study. FB, HM, PYO, BP, CD, AS, EY, DC, AC, MC, HR, and FM conducted the study on enrolled patients. FB, JCR, PYO, CD, BP, EY, LP, AL, MC, and AM analyzed the data. FB and JCR interpreted the data and wrote the first draft of the manuscript. All authors contributed to drafting of the work a... | PMC10476380 | |
Funding | Some equipment used in this work was graciously provided by GE Healthcare. EY, CD, and DC received a 1‐year research fellowship grant from the University Hospital of Angers, France. BP received a 1‐year research fellowship grant from the University Hospital of Réunion, France. | PMC10476380 | ||
Availability of data and materials | The datasets analyzed during the current study are available from the corresponding author on reasonable request. | PMC10476380 | ||
Declarations | PMC10476380 | |||
Ethics approval and consent to participate | The study was performed in accordance with the ethical standards of the Declaration of Helsinki. It was approved by the appropriate legal and ethical authorities (ethics committee Sud-Est I, # 2017-A02842-51). Oral consent was obtained from all patients’ relatives after oral and written information. | PMC10476380 |
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