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The Cochrane Database of Systematic... Nov 2023A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines.
OBJECTIVES
To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo.
DATA COLLECTION AND ANALYSIS
Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses.
MAIN RESULTS
Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low.
AUTHORS' CONCLUSIONS
In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.
Topics: Adult; Humans; Panic Disorder; Selective Serotonin Reuptake Inhibitors; Paroxetine; Fluoxetine; Venlafaxine Hydrochloride; Serotonin and Noradrenaline Reuptake Inhibitors; Alprazolam; Clomipramine; Reboxetine; Clonazepam; Desipramine; Network Meta-Analysis; Antidepressive Agents; Antidepressive Agents, Tricyclic; Benzodiazepines; Diazepam
PubMed: 38014714
DOI: 10.1002/14651858.CD012729.pub3 -
Psychiatry and Clinical... Sep 2023Gray matter alterations play a role in the panic disorder's pathophysiology origin. However, the current literature seemed inadequate to reach a consistent conclusion....
BACKGROUND
Gray matter alterations play a role in the panic disorder's pathophysiology origin. However, the current literature seemed inadequate to reach a consistent conclusion. Therefore, we conducted this gray matter meta-analysis on panic disorder.
METHODS
A systematic review and a voxel-wise meta-analysis based on voxel-based morphometry were conducted for the gray matter studies in patients with panic disorder. The Seed-based d Mapping toolbox was applied for the voxel-wise meta-analysis. Fourteen gray matter studies (954 subjects) were enrolled in the current meta-analysis. The subgroup analysis of typical-onset versus late-onset patients was also performed. At last, the clinical severity was meta-regressed with gray matter alterations.
RESULTS
Significant gray matter alterations were found in the left para-cingulate gyrus and the right amygdala of panic disorder patients. The subgroup analysis of typical-onset panic disorder patients showed a similar pattern. However, gray matter alterations were demonstrated in the bilateral opercular cortex of late-onset panic disorder patients. A significant association between the clinical severity and the gray matter alterations was found in the fronto-cingulate regions of panic disorder patients.
CONCLUSION
Gray matter alterations might represent a significant pillar of panic disorder's neurobiology, especially for the amygdala, cingulate, and frontal regions. Future gray matter studies in panic disorder should be needed to reconfirm this pattern of gray matter alterations.
PubMed: 38765308
DOI: 10.5152/pcp.2023.23684 -
Psychopharmacology Nov 2023Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and... (Meta-Analysis)
Meta-Analysis Review
RATIONALE
Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known.
OBJECTIVE
We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear.
METHODS
We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments.
RESULTS
Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes.
CONCLUSIONS
This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs.
Topics: Animals; Humans; Selective Serotonin Reuptake Inhibitors; Bayes Theorem; Fear; Anxiety Disorders; Stress Disorders, Post-Traumatic
PubMed: 36847831
DOI: 10.1007/s00213-023-06333-7 -
JAMA Network Open Nov 2023Anxiety disorders are associated with poor maternal and neonatal outcomes. Women in low- and middle-income countries (LMICs) are thought to be disproportionally burdened... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Anxiety disorders are associated with poor maternal and neonatal outcomes. Women in low- and middle-income countries (LMICs) are thought to be disproportionally burdened by these disorders, yet their prevalence is unclear.
OBJECTIVE
To conduct a systematic review and meta-analysis to determine the prevalence of 6 anxiety and related disorders among perinatal women in LMICs.
DATA SOURCES
Embase, MEDLINE, PsycINFO, Cochrane Library, CINAHL, and Web of Science databases were searched from inception until September 7, 2023.
STUDY SELECTION
Studies conducted in World Bank-defined LMICs and reporting prevalence of generalized anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, posttraumatic stress disorder, panic disorder, or adjustment disorder during the perinatal period (conception to 12 months post partum) using a validated method were included.
DATA EXTRACTION AND SYNTHESIS
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Study eligibility, extracted data, and risk of bias of included studies were assessed by 2 independent reviewers. Random-effects meta-analysis was used to estimate pooled point prevalence. Subgroup analyses were performed by specific anxiety disorder.
MAIN OUTCOMES AND MEASURES
Main outcomes were prevalence estimates of each anxiety disorder, measured as percentage point estimates and corresponding 95% CIs.
RESULTS
At total of 10 617 studies were identified, 203 of which met the inclusion criteria and reported the outcomes of 212 318 women from 33 LMICs. Generalized anxiety disorder was the most reported (184 studies [90.6%]) and most prevalent disorder at 22.2% (95% CI, 19.4%-25.0%; n = 173 553). Posttraumatic stress disorder was the second most prevalent (8.3%; 95% CI, 5.0%-12.2%; 33 studies; n = 22 452). Adjustment disorder was least prevalent (2.9%; 95% CI, 0.0%-14.1%; 2 studies; n = 475). The prevalence of generalized anxiety varied by country income status, with the highest prevalence among lower-middle-income countries (27.6%; 95% CI, 21.6%-33.9%; 59 studies; n = 25 109), followed by low-income (24.0%; 95% CI, 15.3%-33.8%; 11 studies; n = 4961) and upper-middle-income (19.1%; 95% CI, 16.0%-22.4%; 110 studies; n = 138 496) countries.
CONCLUSIONS AND RELEVANCE
These findings suggest that 1 in 5 women living in LMICs experience anxiety disorders during pregnancy and post partum. Targeted action is needed to reduce this high burden.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Developing Countries; Prevalence; Anxiety Disorders; Anxiety; Stress Disorders, Post-Traumatic
PubMed: 37976063
DOI: 10.1001/jamanetworkopen.2023.43711 -
World Psychiatry : Official Journal of... Jun 2024Psychotherapies are first-line treatments for most mental disorders, but their absolute outcomes (i.e., response and remission rates) are not well studied, despite the...
Psychotherapies are first-line treatments for most mental disorders, but their absolute outcomes (i.e., response and remission rates) are not well studied, despite the relevance of such information for health care users, providers and policy makers. We aimed to examine absolute and relative outcomes of psychotherapies across eight mental disorders: major depressive disorder (MDD), social anxiety disorder, panic disorder, generalized anxiety disorder (GAD), specific phobia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and borderline personality disorder (BPD). We used a series of living systematic reviews included in the Metapsy initiative (www.metapsy.org), with a common strategy for literature search, inclusion of studies and extraction of data, and a common format for the analyses. Literature search was conducted in major bibliographical databases (PubMed, PsycINFO, Embase, and the Cochrane Register of Controlled Trials) up to January 1, 2023. We included randomized controlled trials comparing psychotherapies for any of the eight mental disorders, established by a diagnostic interview, with a control group (waitlist, care-as-usual, or pill placebo). We conducted random-effects model pairwise meta-analyses. The main outcome was the absolute rate of response (at least 50% symptom reduction between baseline and post-test) in the treatment and control conditions. Secondary outcomes included the relative risk (RR) of response, and the number needed to treat (NNT). Random-effects meta-analyses of the included 441 trials (33,881 patients) indicated modest response rates for psychotherapies: 0.42 (95% CI: 0.39-0.45) for MDD; 0.38 (95% CI: 0.33-0.43) for PTSD; 0.38 (95% CI: 0.30-0.47) for OCD; 0.38 (95% CI: 0.33-0.43) for panic disorder; 0.36 (95% CI: 0.30-0.42) for GAD; 0.32 (95% CI: 0.29-0.37) for social anxiety disorder; 0.32 (95% CI: 0.23-0.42) for specific phobia; and 0.24 (95% CI: 0.15-0.36) for BPD. Most sensitivity analyses broadly supported these findings. The RRs were significant for all disorders, except BPD. Our conclusion is that most psychotherapies for the eight mental disorders are effective compared with control conditions, but absolute response rates are modest. More effective treatments and interventions for those not responding to a first-line treatment are needed.
PubMed: 38727072
DOI: 10.1002/wps.21203 -
Journal of Affective Disorders Mar 2024Anxiety-related disorders feature elevated negative affect (NA), and in some cases, diminished positive affect (PA). It remains unclear how well extant psychotherapies... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Anxiety-related disorders feature elevated negative affect (NA), and in some cases, diminished positive affect (PA). It remains unclear how well extant psychotherapies for anxiety-related disorders improve PA versus NA.
METHODS
We systematically searched the Cochrane Central Register of Controlled Trials, PubMed, PsychInfo, and Web of Science databases. Records included studies involving (1) patients with a principal or co-principal diagnosis of at least one anxiety-related disorder (i.e., generalized anxiety, social anxiety, panic, agoraphobia, health anxiety, specific phobia, obsessive-compulsive disorder, or posttraumatic stress disorder), and (2) pre- and post-treatment PA and NA scores or a change index between pre- and post-treatment PA and NA scores. Effect sizes were calculated for meta-analyses.
RESULTS
Fourteen studies with 1001 adults with an anxiety-related disorder were included. Psychotherapeutic interventions included cognitive behavioral, present-centered, and imagery-based approaches. Treatments reduced NA (g = -0.90; 95%CI [-1.19, -0.61]) to a greater extent than they improved PA (g = 0.27; 95%CI [0.05, 0.59]), Z = -5.26, p < .001. The limited number of studies available precluded analyses of the relationship between changes in affect and symptoms.
LIMITATIONS
Results should be considered with caution given the small number and heterogeneity of included studies.
CONCLUSIONS
Current psychotherapeutic interventions for anxiety-related disorders may not improve PA and NA to comparable levels.
Topics: Adult; Humans; Anxiety Disorders; Phobic Disorders; Psychotherapy; Agoraphobia; Anxiety; Psychotropic Drugs
PubMed: 38211753
DOI: 10.1016/j.jad.2024.01.086 -
Neuropsychopharmacology Reports Sep 2023Previous behavioral pharmacology studies involving rodents suggested riluzole had potential to be an ideal psychotropic drug for psychiatric disorders with anxiety or... (Review)
Review
AIM
Previous behavioral pharmacology studies involving rodents suggested riluzole had potential to be an ideal psychotropic drug for psychiatric disorders with anxiety or fear as primary symptoms. Several clinical studies have recently been conducted. The purpose of this study was to gather information about the efficacy and tolerability of riluzole for patients with those symptoms.
METHODS
We searched PubMed, PsycINFO, CINAHL, EMBASE, and the Cochrane database from inception until April 2021, and performed manual searches for additional relevant articles. This review included: (1) studies involving participants that were patients with generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, or phobias; and (2) randomized controlled trials (RCTs) or intervention studies (e.g., single arm trials) examining the effects and safety of riluzole.
RESULTS
Of the 795 identified articles, four RCTs, one RCT subgroup-analysis, and three open-label trials without control groups met the inclusion criteria. Most trials evaluated the efficacy of riluzole as an augmentation therapy with selective serotonin reuptake inhibitors and other antidepressants for PTSD, OCD, or GAD. However, there was insufficient evidence to confirm the effects of riluzole for patients with these psychiatric disorders. Most trials demonstrated adequate study quality.
CONCLUSIONS
This review found insufficient evidence to confirm the effects of riluzole for psychiatric disorders with anxiety or fear as primary symptoms. It would be worthwhile to conduct studies that incorporate novel perspectives, such as examining the efficacy of riluzole as a concomitant medication for psychotherapy.
Topics: Humans; Riluzole; Anxiety Disorders; Anxiety; Obsessive-Compulsive Disorder; Fear
PubMed: 37463744
DOI: 10.1002/npr2.12364 -
Journal of Behavior Therapy and... Dec 2023Anxiety disorders are the most prevalent mental disorders worldwide. Virtual reality (VR) treatment approaches have increasingly been studied. Before clinical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVES
Anxiety disorders are the most prevalent mental disorders worldwide. Virtual reality (VR) treatment approaches have increasingly been studied. Before clinical implementation, it is necessary to evaluate the treatment effect of VR applications. The objective is to evaluate the treatment effect of virtual reality applications in the treatment of anxiety disorders compared to conventional therapy.
METHODS
A systematic literature review with meta-analysis was conducted. Four databases were used to identify randomized controlled trials published between April 2011 and April 2021 which compare VR applications with non-VR interventions or waiting lists. Study characteristics, pre- and post-treatment data were extracted. Hedges g was calculated as effect size. Primary outcome was anxiety symptoms.
RESULTS
Data from 17 studies from 827 participants was extracted. The studies examined specific phobia (n = 9), social anxiety disorder (n = 4), agoraphobia (n = 2) and panic disorder (n = 2). 16 out of 17 studies used head-mounted displays as VR application. A non-significant effect size with significant heterogeneity was observed in favor of the use of VR applications in anxiety symptoms (g, 0.33; 95%-CI, -0.20-0.87). Compared to passive control groups, VR applications are associated significant with lower anxiety symptoms (g, 1.29; 95%-CI, 0.68-1.90).
LIMITATIONS
The study and patient characteristics varied between the individual studies which is reflected in a high statistical heterogeneity of the effect sizes.
CONCLUSIONS
The added value of VR applications over waiting-list or psychoeducation only control groups is obvious. VR applications can be used as part of the treatment of anxiety disorders, especially when conventional therapy is unavailable.
Topics: Humans; Anxiety Disorders; Phobic Disorders; Phobia, Social; Anxiety; Virtual Reality; Virtual Reality Exposure Therapy; Randomized Controlled Trials as Topic
PubMed: 37453405
DOI: 10.1016/j.jbtep.2023.101893 -
Brain and Behavior Jan 2024The existing literature on the association between brain-derived neurotrophic factor (BDNF) protein levels and panic disorder presents inconsistent findings. This... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The existing literature on the association between brain-derived neurotrophic factor (BDNF) protein levels and panic disorder presents inconsistent findings. This systematic review and meta-analysis aim to synthesize the available evidence and determine the overall effect of BDNF protein levels in individuals diagnosed with panic disorder.
METHODS
A comprehensive literature search was conducted using electronic databases (PubMed, Embase, Scopus, PsycINFO, and Web of Science) from inception to April 21, 2023. The search strategy included relevant keywords and medical subject headings terms related to BDNF, panic disorder, and protein levels. A random-effects model was used for the meta-analysis, and subgroup analyses were performed to explore heterogeneity. Publication bias was assessed using funnel plots and statistical tests.
RESULTS
A total of 12 studies met the inclusion criteria. The meta-analysis demonstrated a significant decrease in BDNF protein levels in individuals with panic disorder (SMD = -.53, 95% CI: -1.02 to -.04, p < .001; I : 92%). The results of subgroup and meta-regression analyses were not statistically significant. No significant publication bias was observed based on the results of Egger's regression test (p-value = .3550).
CONCLUSION
This systematic review and meta-analysis provide evidence of lower BDNF protein levels in individuals diagnosed with panic disorder compared to healthy controls. The findings suggest a potential role for BDNF dysregulation in the pathophysiology of panic disorder. Further research is warranted to elucidate the underlying mechanisms and potential therapeutic implications.
Topics: Humans; Panic Disorder; Brain-Derived Neurotrophic Factor; Regression Analysis
PubMed: 38376041
DOI: 10.1002/brb3.3349 -
Public Health Feb 2024To update an earlier review, published in 2016, on the health and other outcomes associated with children and young people's consumption of energy drinks (EDs). (Review)
Review
OBJECTIVE
To update an earlier review, published in 2016, on the health and other outcomes associated with children and young people's consumption of energy drinks (EDs).
STUDY DESIGN
Review article.
SYSTEMATIC REVIEW
Systematic searches of nine databases (ASSIA, CINAHL, Cochrane Library, DARE, Embase, ERIC, MEDLINE, PsycINFO and Web of Science) retrieved original articles reporting the effects of EDs experienced by children and young people up to the age of 21 years. Searches were restricted by publication dates (January 2016 to July 2022) and language (English). Studies assessed as being weak were excluded from the review. Included studies underwent narrative synthesis.
RESULTS
A total of 57 studies were included. Boys consumed EDs more than girls. Many studies reported a strong positive association between ED consumption and smoking, alcohol use, binge drinking, other substance use and the intentions to initiate these behaviours. Sensation-seeking and delinquent behaviours were positively associated with ED consumption, as were short sleep duration, poor sleep quality and low academic performance. Additional health effects noted in the updated review included increased risk of suicide, psychological distress, attention-deficit hyperactivity disorder symptoms, depressive and panic behaviours, allergic diseases, insulin resistance, dental caries and erosive tooth wear.
CONCLUSIONS
This review adds to the growing evidence that ED consumption by children and young people is associated with numerous adverse physical and mental health outcomes. Where feasible and ethical, additional longitudinal studies are required to ascertain causality. The precautionary principle should be considered in regulatory policy and restriction of ED sales to this population.
PROSPERO REGISTRATION
CRD42021255484.
Topics: Child; Male; Female; Humans; Adolescent; Young Adult; Adult; Energy Drinks; Dental Caries; Alcohol Drinking; Substance-Related Disorders; Smoking
PubMed: 38228408
DOI: 10.1016/j.puhe.2023.08.024