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Trial Registration
ClinicalTrials.gov Identifier:
PMC10308298
Introduction
psychotic symptoms, Psychosis, First-episode psychosis, psychosis
REMISSION
First-episode psychosis is typically preceded by a prodrome characterized by nonspecific and attenuated psychotic symptoms and functional impairment. Ultrahigh risk criteria were introduced to prospectively identify this prodromal period.Unraveling the heterogeneity in the ultrahigh risk population is paramount to iden...
PMC10308298
Methods
PMC10308298
Study Design and Setting
The SMART design comprised 3 steps: open-label SPS (6 weeks), SPS vs CBCM (20 weeks), and CBCM with fluoxetine vs CBCM with placebo (26 weeks) (eFigure 1 in
PMC10308298
Participants
Prodromal Questionnaire-16
Individuals seeking treatment were eligible for trial inclusion if they were aged 12 to 25 years, met ultrahigh risk criteria,Participants were screened using a standardized clinical assessment and the Prodromal Questionnaire-16 (PQ-16).
PMC10308298
Randomization
Depression
REMISSION, BLIND
Randomization was based on computer-generated treatment allocations prepared by independent personnel. Participants who met remission criteria at the end of step 1 were randomized to SPS or monitoring; those who did not remit were randomized to CBCM or SPS. Assessors were blind to treatment allocation. Participants in ...
PMC10308298
Treatments
PMC10308298
Monitoring
Clinicians monitored participants’ mental state and risk at 3, 6, 9, and 12 months postentry to step 1. Any deterioration in mental health was appropriately managed.
PMC10308298
SPS
REMISSION
Manualized supportive counseling and problem-solving strategies were delivered within a positive psychology framework. Sessions were 30 to 50 minutes (weekly to fortnightly). In the relapse prevention and remission trial arm, participants received monthly SPS for up to 12 months.
PMC10308298
CBCM
CBCM, a specialized manualized psychosocial intervention, consisted of cognitive behavioral therapy (CBT) provided within a case management framework.
PMC10308298
Medications
Step 3 comprised 1 capsule of fluoxetine, 20 mg per day, or placebo, increasing to 40 mg per day or 2 placebo capsules after 6 weeks if clinical response was insufficient as judged by the treating psychiatrist. At 12 weeks, a fast-fail option was available for participants who had deteriorated or had not responded to t...
PMC10308298
Outcome Measures
For power purposes and sample size calculation,Other outcome measures included the Brief Psychiatric Rating Scale (BPRS);Therapy sessions were audio recorded with consent and independently rated for fidelity. Based on the minimum number of sessions provided for each treatment at each step,
PMC10308298
Statistical Analysis
The study was powered to detect a small to medium effect size (Cohen
PMC10308298
Results
PMC10308298
Participant Flow
Of 1343 individuals considered, 342 were included (198 female; mean [SD] age, 17.7 [3.1] years) (
PMC10308298
Sample Demographic Characteristics at Baseline
Depression, perceptual abnormalities
Abbreviations: BPRS, Brief Psychiatric Rating Scale; CAARMS, Comprehensive Assessment of At-Risk Mental States; MADRS, Montgomery-Åsberg Depression Rating Scale; PACE, Personal Assessment and Crisis Evaluation; SANS, Scale for the Assessment of Negative Symptoms; SPS, support and problem solving; SOFAS, Social and Occu...
PMC10308298
CONSORT Diagram
Discontinuation rates were 17.8% (61 of 342; step 1), 47.7% (134 of 281; step 2), and 38.4% (53 of 138; step 3). Reasons for discontinuation are listed in eTable 1 in
PMC10308298
Hypothesis 1: Remission Rates
REMISSION
Remission rates (ie, sustained remission) across treatment arms at the end of steps 1, 2, and 3 were 8.5%, 10.3%, and 11.4%, respectively. The overall remission rate (ie, sustained remission at the end of at least one step) was 27.2%. There were no significant differences in remission rates between treatments at the en...
PMC10308298
Hypothesis 2a: Effect of CBCM on Functioning and Clinical Measures
For the primary outcome, intent-to-treat analysis revealed no significant difference in mean scores on the Global Functioning: Social and Role scales between SPS and CBCM at 6 months (
PMC10308298
General Linear Model Analysis Comparing Cognitive-Behavioral Case Management (CBCM) and Support and Problem Solving (SPS) at 6 Months and CBCM With Fluoxetine and CBCM With Placebo at 12 Months
Depression, perceptual abnormalities
INTERACTION
Abbreviations: AQoL, Assessment of Quality of Life; BPRS, Brief Psychiatric Rating Scale; CAARMS, Comprehensive Assessment of At-Risk Mental States; DACOBS, Davos Assessment of Cognitive Biases Scale; DS, disorganized speech; GF, Global Functioning Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; NBI, nonbizarr...
PMC10308298
Hypotheses 2b and 2c: Effect of Baseline Cognitive Biases or Vulnerabilities on Remission and Treatment Outcome
While this hypothesis was intended to be restricted to the CBCM group, CBCM did not produce superior outcomes or greater improvement on cognitive biases or vulnerabilities than SPS (The correlation between baseline DACOBS total and 6-month outcomes and between change in DACOBS total and change in outcomes among those w...
PMC10308298
Hypothesis 3: Effect of Antidepressant Medication on Clinical Outcome
Both treatment arms (CBCM with fluoxetine and CBCM with placebo) showed improvement by the end of step 3, with no significant difference on any measure (
PMC10308298
Changes in Mean Symptom and Functioning Scores From Baseline to the End of Step 3
Depression
Circles represent individual participant data. Fluoxetine or placebo commenced at 6 months (start of step 3). AQoL indicates assessment of quality of life; BPRS, Brief Psychiatric Rating Scale; CBCM, cognitive-behavioral case management; DACOBS, Davos Assessment of Cognitive Biases Scale; MADRS, Montgomery-Åsberg Depre...
PMC10308298
Hypothesis 4: Relapse Rates and Outcomes of Participants Who Remitted
Six-month relapse rates were higher in the SPS group (59.8%) than monitoring (16.9%) among participants who remitted at step 1 (Six-month SOFAS scores significantly differed between SPS and monitoring among participants who remitted at step 1 (effect size, 0.91; 95% CI, 0.95-19.6;
PMC10308298
Transition to Psychosis
The Kaplan-Meier–estimated 12-month transition rate was 13.5% (95% CI, 9.1-18.0). The log-rank test indicated no significant difference between groups at 6 and 12 months (
PMC10308298
Overall Treatment Effect and Complete-Case and Per-Protocol Analyses
Across the entire sample, small to medium effect sizes were found at 6 and 12 months on measures of symptoms and functioning (eTable 6 in
PMC10308298
Treatment Adherence and Fidelity
The mean (SD) number of sessions attended was 2.3 (1.5) and 5.7 (3.9) for SPS at steps 1 and 2, respectively, and 6.2 (3.7) at step 2 and 6.0 (4.2) at step 3 for CBCM. A total of 199 recordings (65 participants; 24 clinicians) were rated for fidelity, a mean (SD) of 3.1 (2.1) per participant and 8.3 (9.3) per clinician...
PMC10308298
Adverse Events
ADVERSE EVENTS
Few adverse and serious adverse events occurred. No significant group differences were observed (eTable 17 in
PMC10308298
Discussion
STAR*D, Depression, psychosis
SECONDARY, REMISSION
This is the first SMART trial to be conducted in the ultrahigh risk population. The primary outcome of functioning at the end of step 2 was selected for sample size and power calculations; however, results should be considered as a whole, spanning all steps. For the primary outcome, there was no difference between CBCM...
PMC10308298
Strengths and Limitations
psychosis
To our knowledge, this is the largest ultrahigh risk for psychosis trial to date, reflecting the utility of primary care youth mental health platforms, particularly when recruiting medication-naive participants. However, the treatment provided was insufficient for a large proportion of our sample. Despite high dropout ...
PMC10308298
Conclusions
REMISSION
Enhancing the intensity of treatment with psychological interventions or medications was challenging to implement with fidelity and adherence in this largely primary care-based sample but nevertheless could not be demonstrated to produce any benefit over and above continuing a simpler form of care. Low remission and hi...
PMC10308298
References
REMISSION
Trial protocolClick here for additional data file.eMethodseTable 1. Reasons for treatment discontinuation (%)eTable 2. Pearson correlation between baseline DACOBS total and 6-month outcomes and between change in DACOBS total and change in outcomes (Step 1 non-remitters)eTable 3. 12-month outcomes of the fast-fail group...
PMC10308298
Methods
We leveraged the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) trial, a randomized double-blind placebo-controlled trial of antimicrobial therapy with azithromycin and nitazoxanide provided quarterly to infants from 6 to 15 months of age. We tested 5,479 stool samples at time points...
PMC10734999
Results
There was substantial carriage of enteropathogens in stool. Azithromycin administration led to reductions in
PMC10734999
Conclusion
infections
INFECTIONS
The antimicrobial intervention of quarterly azithromycin plus or minus nitazoxanide led to only transient decreases in enteric infections with
PMC10734999
Data Availability
All relevant data are within the paper and its
PMC10734999
Introduction
infections
CNS INFECTIONS, INFECTIONS
Early enteric infections in children in low-resource settings are an established risk factor for poor growth [This background formed the rationale for the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) trial, a randomized double-blind placebo-controlled trial of antimicrobial therapy...
PMC10734999
Methods
PMC10734999
Study enrollment and interventions
The ELICIT study methods have been previously reported in detail [
PMC10734999
Data and sample collection
Use of non-study antibiotics by study children, defined as any antibiotic that was not part of the study intervention, was identified using a standardized questionnaire at monthly visits. Child lengths using measuring boards and weights using digital scales were measured every three months. Stool samples were collected...
PMC10734999
Stool testing
Procedures for sample extraction and testing have been previously detailed [
PMC10734999
Statistical analysis
enteric infection
REGRESSION
Pathogens with an overall prevalence of at least 5% were included in the analyses of pathogen carriage. At a prevalence of 5% in the placebo arm, we had 80% power to detect a prevalence in the antimicrobial arm of 1.8%, a 3.2% difference; at a prevalence of 20%, we had 80% power to detect a prevalence of 13.6% in the a...
PMC10734999
Results
The baseline characteristics of the children in this study are summarized in
PMC10734999
Sample testing by qPCR, receipt of non-study antibiotics, and anthropometry by intervention arm.
There was substantial detection of enteric pathogens as we have noted previously [
PMC10734999
Overall pathogen prevalence in the stool of ELICIT children at 6, 12, and 18 months by qPCR.
enteropathogen, enteroaggregative
Y axis shows prevalence or proportion positive. EAEC = enteroaggregative We examined the effect of receiving study antimicrobial versus placebo on enteropathogen carriage.
PMC10734999
Difference in enteropathogen detection in the antibiotic versus placebo arms at 6, 6.5, 12, 12.5, and 18 months.
PENICILLINS
X axis is the absolute difference in pathogen prevalence between the antibiotic and placebo arms. Negative values to the left of 0.0 represent lower carriage in the active arm.Because children frequently received non-study antibiotics, we examined the effect of receiving such antibiotics on pathogens as well. Penicilli...
PMC10734999
Difference in pathogen detection in children that recently received non-study antibiotics.
X axis is the absolute difference in those that received non-study antibiotics during the month prior to 6, 12, and 18 months versus those that did not receive non-study antibiotics. Negative values to the left of 0.0 represent lower carriage with receipt of non-study antibiotics.We examined whether a growth benefit wa...
PMC10734999
Difference in 3 month growth outcomes by treatment arm stratified by pathogen detection at 6 and 12 months of age.
Shown are the subset of children at 6 and 12 months with We also tested for carriage of antimicrobial resistance genes by qPCR within this customized TAC card. Receiving antimicrobials rather than placebo slightly increased the risk of detecting the macrolide resistance genes
PMC10734999
Discussion
ETEC diarrhea, intestinal infections, infections, reinfections, ETEC
INFECTIONS, INTESTINAL INFECTIONS
The ELICIT trial administered single-dose azithromycin plus or minus nitazoxanide quarterly to infants under the hypothesis that antibiotic treatment of the intestinal infections associated with poor growth could reduce child stunting. In the primary analysis no effect on childhood growth or stunting was seen at 18 mon...
PMC10734999
Supporting information
PMC10734999
Pathogens and gene targets tested by PCR in this study.
(DOCX)Click here for additional data file.
PMC10734999
Complete ELICIT TAC data.
(CSV)Click here for additional data file.
PMC10734999
ELICIT TAC data dictionary.
(CSV)Click here for additional data file.
PMC10734999
Difference in pathogen detection in the nicotinamide versus placebo arms at 6, 6.5, 12, 12.5, and 18 months.
X axis is the absolute reduction in pathogen prevalence between the nicotinamide–placebo. Negative values to the left of 0.0 represent reduction with nicotinamide. 95% confidence intervals are included.(DOCX)Click here for additional data file.
PMC10734999
Prevalence of non-study antibiotic use by drug class and month.
(DOCX)Click here for additional data file.
PMC10734999
References
PMC10734999
Background
’ learning
Medical trainees often encounter situations that trigger emotional reactions which may hinder learning. Evidence of this effect on medical trainees is scarce and whether it could be counteracted is unclear. This study investigated the effect of negative emotions on medical residents’ learning and whether cognitive reap...
PMC9883942
Methods
Ninety-nine medical residents participated in a three-phase experiment consisting of: (1)
PMC9883942
Results
Study time significantly varied between conditions (
PMC9883942
Conclusion
Negative emotions can adversely affect medical residents’ learning. The effect of emotions was not counteracted by cognitive reappraisal, which has been successfully employed to regulate emotions in other domains. Further research to examine emotion regulation strategies appropriate for medical education is much needed...
PMC9883942
Supplementary Information
The online version contains supplementary material available at 10.1186/s12909-022-03996-2.
PMC9883942
Keywords
PMC9883942
Background
anger, ’ learning
Emotionally difficult situations are unavoidable in medical training. Students and doctors have reported experiencing negative emotions such as sadness when watching a patient’s suffering, fear of making mistakes, or anger when witnessing colleagues’ unprofessional behaviour [How could emotions affect residents’ learni...
PMC9883942
Methods
PMC9883942
Design
This study was an experiment consisting of three tasks: (I) an Experiment design and tasks flow
PMC9883942
Participants
Participants were ninety-nine first-year internal medicine residentsAll participants signed informed consent forms. The study protocol was approved by the Research Ethics Committee of the São Paulo University (659.347 in 21/05/2014).
PMC9883942
Materials and procedure
The study was presented to the participants as two separate, unrelated studies, from two different institutions. The emotion induction procedure was presented as a study on the use of fictitious videoclips in medical education whereas the learning task and the test were purportedly a study on the suitability of new med...
PMC9883942
Emotion induction procedure
We opted to use a vicarious experience to induce negative emotions for ethical reasons. Experimental research has commonly employed films to elicit standardized emotional responses [After watching the videoclip, participants answered 6 questions to check if our manipulation worked (Additional file Subsequently, partici...
PMC9883942
Learning task
SCHMIDT, CARDIAC ARREST
After completing the above-mentioned tasks (purportedly, Study 1) participants were requested to open the second envelope (purportedly, Study 2), which contained a 930-word text on oxidative damage during cardiac arrest. The text was prepared to by considering the participants’ prior knowledge to avoid ceiling effects ...
PMC9883942
Testing task
After completing the learning task, the participants were requested to write down everything that they could remember from the text. Learning about a certain topic progresses through the enrichment of the semantic network of concepts related to that topic stored in the person’s memory. The more effective the learning, ...
PMC9883942
Data analysis
Sample uniformity between the three experimental conditions with respect to gender and age was checked by performing, respectively, a chi-square test and a one-way ANOVA. Participants’ familiarity with the situation portrayed in the videoclips (item #1 Additional file Two measurements checked our manipulation: the aver...
PMC9883942
Discussion
’ learning [, cognitive reappraisal, ’
This experimental study had a two-fold purpose: (1) examining whether the finding of a previous study [What concerns the first study purpose, these results are in line with findings of a previous study that showed participants under the influence of negative emotions to invest less time to study the learning material a...
PMC9883942
Conclusion
’ learning
Summing up, the present study replicates previous findings that negative emotions adversely impact medical residents’ subsequent learning. To get a better understanding of how to manage this effect, further research is called for. Apparently, these emotional states are harder to regulate than we assumed. Our ER interve...
PMC9883942
Acknowledgements
This study could not have been performed without the help and cooperation of the medical residents at the School of Medicine at University of Sao Paulo, Brazil (2017) for their participation and effort in completing the study tasks.We also thank Dr Chin An Lin for his valuable advice and cooperation and the preceptors ...
PMC9883942
Authors’ contributions
TK contributed to the conception and design of the study, the data collection, analysis and interpretation, drafted the first version of the manuscript and revised the manuscript. SM contributed to the conception and design of the study, the data analysis and interpretation, critically revised the manuscript for import...
PMC9883942
Authors’ information
Erasmus, psychiatric
SCHMIDT
Telma Kremer, MSc, PhD is a clinical psychologist graduated at São Paulo University, with a Master in Health Professions Education from Maastricht University and a PhD at the Institute of Medical Education Research Rotterdam, Erasmus MC, The Netherlands.Sílvia Mamede, MD, PhD, is associate professor at the Institute of...
PMC9883942
Funding
None.
PMC9883942
Availability of data and materials
The data analysed during the present study are available from the corresponding author upon reasonable request.
PMC9883942
Declarations
PMC9883942
Ethics approval and consent to participate
All participants signed informed consent forms. The study protocol was approved by the Research Ethics Committee of the São Paulo University (659.347 in 21/05/2014). All methods were performed in accordance with the relevant guidelines and regulations.
PMC9883942
Consent for publication
Not applicable.
PMC9883942
Competing interests
The authors declare that they have no competing interests.
PMC9883942
References
PMC9883942
Background
emphysema
LUNG, EMPHYSEMA
Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (BLVR) with endobronchial valves can improve outcomes in appropriately selected patients with emphysema. However, no direct comparison data exist to inform clinical decision making in people who appear suitable for both procedures. Our aim was...
PMC10133584
Methods
airflow obstruction, lung volume reduction, dyspnoea
DISEASE
This multicentre, single-blind, parallel-group trial randomised patients from five UK hospitals, who were suitable for a targeted lung volume reduction procedure, to either LVRS or BLVR and compared outcomes at 1 year using the i-BODE score. This composite disease severity measure includes body mass index, airflow obst...
PMC10133584
Results
88 participants (48% female, mean±
PMC10133584
Introduction
death, lobar atelectasis, COPD, heterogeneous emphysema
COPD
COPD is a common and often disabling condition which is now the third largest cause of death worldwide [An alternative lung volume reduction approach is endobronchial placement of valves to the airways supplying the most emphysematous lobe causing it to deflate. This form of bronchoscopic lung volume reduction (BLVR) c...
PMC10133584
Methods
PMC10133584
Study design and participants
airflow obstruction, COPD
COPD
The CELEB study was a multicentre, randomised controlled, parallel-group superiority trial in which patients with COPD who were considered by a lung volume reduction multidisciplinary team (MDT) meeting to be suitable candidates for both forms of targeted lung reduction therapy, and who did not have collateral ventilat...
PMC10133584
Randomisation and masking
Randomisation to the treatment arm occurred only after the MDT meeting and once participants had undergone a fibreoptic bronchoscopy to allow for assessment of the presence of collateral ventilation using the Chartis system. People who were collateral ventilation-positive exited the study as valves would not be effecti...
PMC10133584
Procedures
LVRS, to remove the most emphysematous part of the target lung, was carried out by a thoracic surgeon under general anaesthesia, primarily using either unilateral video-assisted thoracoscopic surgery or unilateral robot-assisted surgery. Where required, an open thoracotomy was performed at the discretion of the surgeon...
PMC10133584
Outcomes
airflow obstruction
DISEASE
The primary outcome for the trial was the between-group difference in i-BODE score from baseline to 12 months post-procedure. This composite measure of disease severity is made up of body mass index (BMI), airflow obstruction (FEV
PMC10133584
Statistical analysis
Sample size calculation was based on a study comparing change in BODE score 3 months post-LVRS between survivors and non-survivors at 5 years [Changes in outcome measures between groups were analysed using independent t-tests where normally distributed, otherwise the Wilcoxon rank-sum (Mann–Whitney) test was used. Trea...
PMC10133584
Results
death, illness or injury, pneumothorax, atelectasis, lung volume reduction, disability/incapacity, deaths, COPD, coronavirus disease 2019
SUBCUTANEOUS EMPHYSEMA, CORONAVIRUS DISEASE 2019, PNEUMOTHORAX, ADVERSE EVENTS, ATELECTASIS, COMPLICATION, ACUTE EXACERBATION OF COPD, COPD, SECONDARY, EVENTS, COMPLICATIONS
Between 16 September 2016 and 22 July 2019, 163 patients were assessed for their eligibility to be enrolled in the trial. Of 149 patients who were screened and thought on the basis of their CT scan to be collateral ventilation-negative, 38 (26%) were collateral ventilation-positive on Chartis assessment and nine (6%) h...
PMC10133584
Discussion
death, emphysema, COPD, pulmonary hypertension, hyperinflation
ADVERSE EVENTS, DISEASE, EMPHYSEMA, COPD, SECONDARY, PULMONARY HYPERTENSION
The CELEB trial is the first randomised controlled trial to compare the effects of LVRS with BLVR. We found that surgery was not substantially superior to bronchoscopic treatment in patients with intact fissures and that both were similarly safe. Both approaches produced a clinically meaningful reduction in hyperinflat...
PMC10133584
Conclusions
COPD
COPD
The results of this study do not support the hypothesis that LVRS is a substantially superior treatment compared with BLVR, in terms of health outcomes achieved 1 year post-procedure. These broadly similar results at 12 months were obtained with a longer length of stay initially for LVRS but with less need for subseque...
PMC10133584
Shareable PDF
COPD
COPD, THORACIC
This one-page PDF can be shared freely online.Shareable PDF Full list of study investigators on the CELEB trial: Royal Brompton Hospital (London): Sara C. Buttery, Winston Banya, Simon Jordan, Samuel V. Kemp, Adam Lewis, Pallav L. Shah, Nicholas S. Hopkinson, Sofina Begum, Michael I. Polkey, Matthew Pavitt, Karthi Srik...
PMC10133584
References
PMC10133584
Introduction
muscle mass, fatigue
BLOOD, DISEASE, CONTRACTIONS
In recent years, electrical muscle stimulation (EMS) devices have been developed as a complementary training technique that is novel, attractive, and time-saving for physical fitness and rehabilitation. While it is known that EMS training can improve muscle mass and strength, most studies have focused on the elderly or...
PMC10586320
Materials and Methods
PMC10586320