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References
PMC10713151
Background
cognitive, affective, and somatic symptoms, depression, depressive symptoms
EVENTS, INFLAMMATORY RESPONSE
Pregnancy and childbirth are significant events in many women’s lives, and the prevalence of depressive symptoms increases during this vulnerable period. Apart from well documented cognitive, affective, and somatic symptoms, stress and depression are associated with physiological changes, such as reduced heart-rate var...
PMC10084615
Methods
depression
PND
This study is a sub-study of a larger RCT, where significant intervention effects were found on perinatal depression (PND) and perceived stress. Participants were recruited through eight maternity health clinics in Stockholm, Sweden. In this sub-study, we included altogether 80 women with increased risk for PND, and bl...
PMC10084615
Results
PND
Participants who received MBCP reported a significantly larger reduction in perceived stress and a significantly larger increase in mindfulness, compared to participants who received the active control treatment. However, in this sub-study, the intervention had no significant effect on PND, inflammatory serum markers o...
PMC10084615
Conclusions
INFLAMMATION
No significant differences were found regarding changes in HRV measures and biomarkers of inflammation, larger studies may be needed in the future.
PMC10084615
Trial registration
ClinicalTrials.gov ID: 
PMC10084615
Keywords
Open access funding provided by Karolinska Institute.
PMC10084615
Background
cognitive, affective, and somatic symptoms, depression, abnormal uterine artery blood-flow
EVENTS, PND, INFLAMMATORY RESPONSE
Pregnancy and childbirth are significant events in many women’s lives, that often entail abrupt lifestyle changes in addition to hormonal and physiological alterations [Exposure to stressful life events [Apart from an array of well documented cognitive, affective, and somatic symptoms (WHO [Importantly, reduced HRV in ...
PMC10084615
Methods
PMC10084615
Sample
This study is a sub-study of a larger RCT, where perceived stress (assessed with the Perceived Stress Scale) was the primary outcome [Flowchart of participants invited, screened, enrolled, and completing the study (CONSORT figure)
PMC10084615
Procedure
Eligible participants were scheduled for an appointment at the MHC for HRV-registration and the baseline questionnaires were completed via an on-line questionnaire that was sent to them via e-mail. Also, participants were referred to a health care centre to leave their blood samples before randomization – they informed...
PMC10084615
Intervention
SESSION
The original 9-week MBCP program was developed in the USA and consists of nine 3-hour long weekly sessions, a full day retreat and a reunion [Overview over the MBCP–curriculum adapted for the present study. Session Theme and practices [
PMC10084615
Active control
In order to control for the effects of social support, psychoeducation and child-birth preparation, the active control condition consisted of a Lamaze program that is widely available in Stockholm (for more details see [
PMC10084615
Serum markers
Tumor Necrosis, TNF-α
PCT, -20
Prior to randomisation, at pregnancy week 20-25, as well as at post-intervention, at pregnancy week 30-35, the participants left blood samples at a health clinic laboratory. 5 ml of blood was collected from each participant and then left to cool down for 30-60 minutes in room temperature before being centrifuged for 10...
PMC10084615
Heart rate variability
ECTOPIC BEATS
ECG assessment was carried out at baseline and post-intervention, in a supine position on a stationary bench. Three ECG electrodes were placed over the left fifth intercostal space, the right fifth intercostal space and over the manubrium. Once the ECG signal was acceptable, participants were informed that they should ...
PMC10084615
Statistical analyses
Independent sample t-tests were used for parametrically distributed data on interval scale level. For non-parametric data the Mann-Whitney U test was used to compare groups. Variables on nominal levels were tested by Fisher´s exact test. Some of the variables were skewed and therefore transformed to their natural logar...
PMC10084615
Results
PMC10084615
Baseline differences between groups in psychometric measures, serum markers and HRV
No significant baseline differences between groups in outcome variable values were found, apart from a-2 microglobulin and IL-6 where higher levels were found in the intervention group at baseline with
PMC10084615
Correlations between psychometric measures and serum markers/HRV at baseline
There was no correlation found between any of the questionnaire target variables and blood sample target variables / HRV at baseline or at post-intervention (analysis performed for all participants together).
PMC10084615
Discussion
PND
In this study, no significant changes in our primary outcomes, inflammatory serum markers or HRV-measures, were found.However, in line with the results from the main study, participants randomized to MBCP reported a significantly larger reduction in perceived stress and a significantly larger increase in mindfulness, c...
PMC10084615
Limitations of the study
This study has both limitations and strengths. A strength is the randomization of participants and the use of an active control intervention. However, we were not able to conduct a sample size calculation for the present study, due to the scarcity of other studies in this research field. Therefore, we cannot be certain...
PMC10084615
Future research
In this study, it was not possible to assess if some of the changes that were detected in biomarkers over time were due to the interventions or if they were naturally occurring during pregnancy. Therefore, it may be of interest to conduct future studies where a third arm with no intervention is included. Also, future s...
PMC10084615
Conclusion
INFLAMMATION
Our results suggest that MBCP is more effective in decreasing perceived stress and increasing levels of mindfulness, compared to a Lamaze childbirth program. However, no significant differences between MBCP and the Lamaze program were found regarding changes in HRV measures and biomarkers of inflammation.
PMC10084615
Acknowledgements
We thank all our participants and the maternity health care clinics who collaborated with us.
PMC10084615
Authors’ contributions
All authors contributed to the study conception and design. Material preparation and data collection were performed by MN, EN and GL. Lab analyses were conducted by MBW, WO, RG and HK. Statistical analysis was conducted by LR and MN. The first draft of the manuscript was written by LR and all authors commented on previ...
PMC10084615
Funding
Open access funding provided by Karolinska Institute. The study was funded by Ekhaga foundation (2013-32) and The Swedish Research Council (2014-10167). The funding sources had no role in the study other than the financing of it.
PMC10084615
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
PMC10084615
Declarations
PMC10084615
Ethics approval and consent to participate
The Stockholm Regional Ethics Committee approved the study (approval number 2012/400-31/4) and written informed consent was obtained from all participants.
PMC10084615
Consent for publication
Not applicable
PMC10084615
Competing interests
GL and MN are MBCP instructors. The other authors declare no competing interests.
PMC10084615
References
PMC10084615
Introduction:
HIGH MYOPIA, DISEASES
Lutein supplementation is beneficial in preventing maculae from developing serious ocular diseases. This study aimed to evaluate the efficacy and safety of lutein administration in patients with high myopia (HM).
PMC10036027
Methods:
In a single-center randomized double-blinded placebo-controlled trial conducted over 24 months, 22 eyes were enrolled in lutein and control groups. Among them, 15 eyes in the lutein group and 13 eyes in the control group completed the study. All patients with HM (axial length > 26.00) were administered lutein (20 mg) o...
PMC10036027
Results:
The baseline MPOD in the control and lutein groups was 0.71 ± 0.21 and 0.70 ± 0.22, respectively. The MPOD in the control and lutein groups at 3 months was 0.70 ± 0.21 and 0.70 ± 0.25, respectively, and at 6 months was 0.66 ± 0.20 and 0.72 ± 0.27, respectively, which was not significantly different from those at baseli...
PMC10036027
Conclusion:
Lutein supplementation showed significant benefits in MPOD augmentation in patients with HM.
PMC10036027
1. Introduction
AMD, Myopia
MYOPIA, EYE DISEASES, COMPLICATIONS, RETINA
The macula in the retina is a yellow-pigmented area at the posterior pole of the eye that allows central vision and provides the most acute visual acuity (VA) and best color identification.Several studies have suggested that dietary supplementation with lutein prevents eye diseases, such as AMD, and improves visual fun...
PMC10036027
2. Methods
PMC10036027
2.1. Design overview
DRUG EFFECT
This single-center, randomized, double-blind, placebo-controlled study was conducted between September 2017 and March 2021. We used placebo as a control to evaluate the efficacy and safety of lutein in patients with HM. The main components of the placebo were safflower oil and a stirring agent that had no drug effect. ...
PMC10036027
2.2. Setting and participants
AMD, cardiovascular disease, comorbid severe primary diseases, vision-affected ocular diseases, allergy, mydriasis, glaucoma
CARDIOVASCULAR DISEASE, ALLERGY, RETINA, GLAUCOMA, DISEASES OF THE LIVER, DISEASES, CEREBROVASCULAR DISEASE
Patients were recruited from the Tokyo Medical and Dental University Hospital. The inclusion criteria were as follows: Japanese origin, AL of eyeball 26.5 mm or more, and less than 30.0 mm; age 20 to 50 years, and patient consent. The exclusion criteria were as follows: comorbid severe primary diseases, such as cardiov...
PMC10036027
2.3. Randomization and masking
Stratified random numbers were generated by statisticians using the SAS version 9.3 software (SAS Institute Inc., Cary, NC), which denoted the drug number as a running serial number for the sample size. The investigator administered the corresponding drugs to participants according to the sequence in which they were en...
PMC10036027
2.4. Outcomes and measurements
ADVERSE EVENTS, SECONDARY
The primary efficacy marker was the change in MPOD after 6 months of administration relative to that at baseline. To improve data accuracy, the MPOD was evaluated at least 3 times. The secondary efficacy markers were change in VA, change in CS, and change in electroretinogram (ERG) measurements (all relative to baselin...
PMC10036027
2.5. Measurement of macular pigment optical density
FLICKER
The MPOD measurements were performed using a standardized protocol based on the psychophysical method of heterochromatic flicker photometry. This protocol had high test–retest reliability (
PMC10036027
2.6. Visual acuity
The VA of the patients was measured with the best refractive correction using the Nidek system Chart SC-1600 (Nidek Co., Aichi, Japan). The best-corrected visual acuity (BCVA) was compared before and after therapy. VA was converted to the logarithm of the minimal angle resolution and analyzed.
PMC10036027
2.7. Contrast sensitivity
The CS was measured using a CSV-1000E contrast testing instrument (Vector Vision, Greenville, OH) at a distance of 2.4 m under standard brightness (85 cd/m
PMC10036027
2.8. Electroretinogram
Full-field ERGs were obtained. The ERG was performed according to the standards of the International Society for Clinical Electrophysiology of Vision.
PMC10036027
2.9. Datasets
The per-protocol set (PPS) was defined a priori in the protocol; therefore, analyses were performed on the PPS for lutein efficacy. For PPS, we excluded patients with poor compliance to the study protocol and those who refused to administer lutein tablets after baseline. In addition, the MPOD value was investigated usi...
PMC10036027
2.10. General analytical principles
Statistical analyses were performed using the SAS 9.3 software. The statistical description of quantitative data included the number of patients, mean, standard deviation, median, maximum, minimum, test statistic, and
PMC10036027
3. Results
PMC10036027
3.1. Patient characteristics
Of the initially enrolled 44 patients with HM (n = 44 eyes), with 22 patients in the lutein and control groups, 5 refused to continue the study, and 11 were excluded. Thus, 28 patients (n = 28 eyes) completed the study as PPS, with 15 (n = 15 eyes) in the lutein group and 13 (n = 13 eyes) in the control group. The part...
PMC10036027
3.2. Changes after treatment
The MPOD values are listed in Table MPOD scores in the 2 groups before and after drug administration using the PPS.Data are expressed as mean (standard deviation).MPOD = macular pigment optical density, PPS = per protocol set.The BCVA (logarithm of minimal angle resolution) values are presented in Table LogMAR visual a...
PMC10036027
3.3. Stratified macular pigment optical density analysis based on axial length
−0.09
MPOD outcomes were further stratified using different AL strategies (Table MPOD scores in the Lutein groups before and after Lutein administration using the PPS.Data are expressed as mean (standard deviation).AL = axial length, PPS = protocol per set.In the AL ≤ 28.25 mm subgroups, the average of AL at baseline was 27....
PMC10036027
3.4. Adverse events
ADVERSE EVENTS, COMPLICATIONS
None of the patients reported any adverse events or complications.
PMC10036027
4. Discussion
age-related degenerative eye diseases, eye disorder, myopia, ocular pathologies, glaucoma, MP
EYE DISORDER, MYOPIA, RETINAL DETACHMENT, GLAUCOMA, COMPLICATIONS
In this RCT, we evaluated the effects of lutein supplementation on MPOD. We observed that lutein supplementation significantly increased the MPOD level over 6 months and might be beneficial in preventing the loss of macular pigments in patients with HM having <28.25 mm of AL. To our knowledge, this is the first prospec...
PMC10036027
5. Conclusions
myopic
To the best of our knowledge, this is the first randomized clinical study to assess the benefits of lutein supplementation in highly myopic individuals. Our findings showed significant benefits of lutein supplementation in MPOD augmentation in patients with HM. As this study included patients who underwent 6 months of ...
PMC10036027
Acknowledgments
The authors would like to thank Aiko Ibuki, Natsumi Miyagawa, and Chihiro Ono for MPOD examination and data collection.
PMC10036027
Abbreviations:
myopic
axial lengthage-related macular degenerationbest-corrected visual acuitychoroidal neovascularizationcycles per degreecontrast sensitivityelectroretinogramhigh myopiamacular pigmentsmacular pigment optical densityper-protocol setvisual acuityThis study was supported by Santen Pharmaceutical Co. Ltd. The sponsor had no c...
PMC10036027
References
PMC10036027
Subject terms
dissociative amnesia, ’s affective circuits, depressed, depersonalization
SECONDARY
Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain’s affective circuits during acute ketamine-induced ASCs wi...
PMC10587184
Introduction
reduction of anterior insula, dissociative amnesia, anxiety, dissociative, psychiatric disorders, amnesia, paranoid thoughts, dissociative depersonalization, hostility
CORTEX, ADVERSE EFFECT
Racemic ketamine (1:1 esketamine: arketamine) is a non-competitive antagonist of the N-methyl-D-aspartate glutamate receptor and an FDA-approved dissociative anesthetic. It was introduced into clinical practice in the US in the 1960’s as a novel agent that could produce effective sedation and analgesia while maintainin...
PMC10587184
Results
The current study compared outcomes between three drug conditions: placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine. We hereafter refer to the results using only placebo and the 0.5 mg/kg condition as “two conditions” (Figs. 
PMC10587184
Ketamine increases dissociative depersonalization, dissociative derealization, and a blissful state in a dose-dependent manner
fits, dissociative depersonalization
As hypothesized, we observed a significant dose-dependent effect of ketamine in dissociative depersonalization (The experience of dissociation under the 0.5 mg/kg ketamine was also captured by free response reports from participants. We recorded narratives from five participants for all three drug conditions. Suppl. Ta...
PMC10587184
Ketamine increases dissociative amnesia, anxiety, and impaired control and cognition in a dose-dependent manner
dissociative amnesia
We observed a significant dose-dependent effect of ketamine in dissociative amnesia (
PMC10587184
Ketamine increases threat-faces-evoked anterior insula and amygdala activity in a dose-dependent manner
We observed dose-dependent effects of ketamine on increasing right anterior insula (
PMC10587184
Ketamine-induced dissociative depersonalization relieves negative brain states assessed by anterior insula activity
dissociative depersonalization
We only tested for mediation effects comparing the 0.5 mg/kg and the placebo conditions, as the 0.05 mg/kg dose did not induce significant change in any mediators or in the neural activity of the right anterior insula or amygdala. Similarly, we only included activity in response to threat faces (and not happy faces) in...
PMC10587184
Ketamine-induced dissociative amnesia exacerbates negative brain states assessed by anterior insula activity
dissociative amnesia
In contrast to depersonalization, ASCs hypothesized to promote negative affective brain states, specifically dissociative amnesia (Fig. 
PMC10587184
Discussion
TRD, dissociative amnesia, ideation, nausea, anxiety, pain, amnesia, Dissociative, MDD, depression, dissociative depersonalization
DISORDER, REMISSION, DETACHMENT, DISORDERS
The present findings advance our understanding of the role of ketamine-induced ASCs in mediating neural changes in the brain’s affective circuitry. In our placebo-controlled, within-participant design which examined nonclinical participants, we conducted multi-modal measurements of dissociation and other ASCs as well a...
PMC10587184
Methods
PMC10587184
Priori power analysis
To estimate the sample size for detecting ketamine’s effect on our primary neural dependent measures of negative affect circuit activation in response to emotional stimuli, we drew on prior reported effect sizes for a prior study in which imaging was similarly undertaken immediately following ketamine infusion in a rep...
PMC10587184
Participants
SD
We recruited from the community 13 nonclinical adult participants aged 18 to 55 years (mean = 33 years, SD = 9.82 years), with an equivalent distribution of self-reported biological sex (female: 54%, male: 46%). The first participant was enrolled on August 19, 2019 and the last participant was enrolled on October 21, 2...
PMC10587184
Visits
emesis, Easypump® ST/LT
In our randomized, cross-over design, participants underwent a total of five visits, including the screening visit, baseline visit, and three infusion visits during which the participants, research coordinator (study assessments), research nurses (peripheral IV catheter placement), and licensed study clinicians (ketami...
PMC10587184
Assessments of dissociation and other ASCs
dissociative amnesia, dissociative depersonalization, anxiety
To address our first objective to test whether specific aspects of dissociation and other altered states of consciousness differed across dose conditions, we utilized the CADSS and the 5D-ASC to assess specific aspects of ketamine-induced dissociation and other ASCs. CADSS is a 23-item clinician-administered questionna...
PMC10587184
Linear mixed effects models and t-test analyses of dose-dependent effects of ketamine on dissociation and other ASCs
5D-ASC-assessed
To examine dose-dependent effects of ketamine on CADSS-assessed subcomponents of dissociation and 5D-ASC-assessed other ASCs, we used linear mixed effects models (LMMs) with dose (placebo, 0.05 mg/kg or 0.5 mg/kg) as the fixed effect and participant as a random effect using the lmer package (
PMC10587184
Acquisition of brain fMRI during a Facial Expressions of Emotion Task (FEET)
Upon completion of the 40-min infusion, participants were transferred to the MRI suite within the Stanford Center for Cognitive and Neurobiological Imaging via a wheelchair to begin scanning at approximately 60 min after initiation of infusion. FEET was collected at approximately 2 hours after initiation of infusion. I...
PMC10587184
Non-conscious FEET fMRI
At all three drug visits, participants non-consciously viewed facial expressions of emotion, during which fMRI data were collected, to probe automatic bottom-up activation of the positive and negative affect circuits
PMC10587184
Analysis of brain FEET fMRI data
PMC10587184
Generating activation maps
Preprocessed data were entered into a general linear model at the individual level using SPM8 (
PMC10587184
FEET neuroimaging data analysis of dose-dependent effects of ketamine on affective neural circuit
anger
To examine our second objective to test the dose-dependent effects of ketamine on brain activity in response to emotional expressions, we conducted a one-way repeated Analysis of Variance in SPM—with dose as the within-participant factor—on the activation maps for threat faces (consisting of both anger and fear faces) ...
PMC10587184
Mediation analysis using an averaged causal mediation effect model
To address our third objective—to test whether specific aspects of ketamine-induced dissociation and other ASCs mediate the effect of dose on acute changes in neural activity during emotional processing—we utilized the Averaged Causal Mediation Effect (ACME) mediation model
PMC10587184
Reporting summary
Further information on research design is available in the 
PMC10587184
Supplementary information
Supplementary InformationPeer Review FileReporting Summary
PMC10587184
Supplementary information
The online version contains supplementary material available at 10.1038/s41467-023-42141-5.
PMC10587184
Acknowledgements
ABUSE
This work was supported by the National Institute of Drug Abuse under award P50DA042012 (Overall PI: K.D., Project 4 PI Project Lead: L.M.W). The sponsor had no role in the study design, data collection and analysis, or manuscript writing. This work was also supported by Stanford’s Clinical and Translational Science Aw...
PMC10587184
Author contributions
L.M.W., B.D.H., B.K. and K.D. conceptualized and designed the study. L.M.H., X.Z. and L.M.W. wrote the manuscript. X.Z. performed the analyses. L.M.H., B.D.H, P.J.vR. and R.H. monitored the ketamine infusions as licensed clinicians. N.J.G. and C.B. acquired the data. T.S., P.J.vR., J.A.Y., C.I.R., B.K. and K.D. critica...
PMC10587184
Peer review
PMC10587184
Data availability
The pre-processed fMRI and questionnaire data are available under restricted access because they contain data acquired to address aims independent from those reported in the present manuscript and thus have not been fully analyzed yet. Access can be obtained on reasonable request by contacting the corresponding author....
PMC10587184
Code availability
The full analysis codes are available at
PMC10587184
Competing interests
Psychiatric
BRAIN
L.M.H. in the past 3 years has served on an advisory board for Roche. T.S. in the past 3 years has reported grants from Pathway Genomics, Stanley Medical Research Institute, Elan Pharma International Limited, Merck and Co., and Sunovion Pharmaceuticals; consulting fees from Allergan, Impel NeuroPharma Inc., Intra-Cellu...
PMC10587184
References
PMC10587184
Summary
PMC10582777
Background
Ivermectin's mosquitocidal effect and
PMC10582777
Methods
The study consisted of a multiple dose stage and a randomized, double-blind, placebo-controlled stage. Adults with asymptomatic
PMC10582777
Findings
ADVERSE EVENTS
Between June 2019 and October 2020, 49 participants were enrolled. Out of the 34 randomized participants, 29 (85%) completed the trial as per protocol. No severe or serious adverse events were observed. The median time to 90% parasite reduction was 24.1 vs. 32.0 h in the ivermectin and placebo groups, respectively (HR ...
PMC10582777
Interpretation
Ivermectin was well tolerated in doses up to 300 μg/kg once daily for three days and asymptomatic
PMC10582777
Funding
This study was funded by the Centre de Recherches Médicales de Lambaréné and the Centre for Tropical Medicine of the Bernhard Nocht Institute for Tropical Medicine.
PMC10582777
Keywords
PMC10582777
Research in context
PMC10582777
Evidence before this study
malaria, plasmodium
MALARIA, ONCHOCERCIASIS, LYMPHATIC FILARIASIS
A search in PubMed on February 1, 2019, using the keywords “malaria”, “plasmodium”, “ivermectin”, “elimination”, “control”, “transmission”, and “safety” was performed that included English, French and German publications that were indexed in the online database with no limit on publication dates. Ivermectin is an estab...
PMC10582777
Added value of this study
This study evaluates the antimalarial effect and safety of ivermectin on
PMC10582777
Implications of all the available evidence
malaria
MALARIA
The data confirm that ivermectin remains a promising candidate to accompany other elimination tools due to its mosquitocidal effect. Participants achieved parasite reduction regardless of the intervention which should be re-evaluated in further clinical trials. Ivermectin administration as malaria treatment interventio...
PMC10582777