Parkinson’s disease is a neurological disease with a rising incidence and prevalence. Patients with Parkinson’s disease may receive antipsychotics, for example, due to Parkinson’s disease psychosis. Parkinson’s disease psychosis is characterised by visual hallucinations and other psychotic symptoms. To date, no systematic review has evaluated the effects of antipsychotics in patients with Parkinson’s disease. Therefore, this review aims to assess the beneficial and harmful effects of antipsychotics for Parkinson’s disease.

This is a protocol for a systematic review. A search specialist will perform a search in major medical databases (eg, MEDLINE (Medical Literature Analysis and Retrieval System Online), EMBASE (Excerpta Medica database), CENTRAL (Cochrane Central Register of Controlled Trials)) and clinical trial registries. Published and unpublished randomised clinical trials comparing antipsychotics to any control (placebo, standard care or other antipsychotics) in patients with Parkinson’s disease will be included. Two review authors will independently extract data and conduct risk of bias assessments with the Cochrane Risk of Bias tool—V.2. Primary outcomes will be all-cause mortality, serious adverse events and significant falls. Secondary outcomes will be hospitalisations, non-serious adverse events, Unified Parkinson’s Disease Rating Scale total score and psychotic symptoms using any valid symptom scale. Data will be synthesised by aggregate meta-analysis, trial sequential analysis and network meta-analysis. Several subgroup analyses are planned. An eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by GRADE (Grading of Recommendations Assessment, Development and Evaluations) and CiNeMA (Confidence in Network Meta-Analysis) approach.

This protocol does not include results, and ethics approval is not required for the project. The findings from the systematic review will be published in international peer-reviewed scientific journals.

PROSPERO ID: CRD42025633985. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD42025633985.

To increase the sustainability of healthcare, clinical trials must assess the environmental impact of interventions alongside clinical outcomes. This should be guided by Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) extensions, which will be developed by The Implementing Climate and Environmental Outcomes in Trials Group. The objective of the scoping review is to describe the existing methods for reporting and measuring environmental outcomes in randomised trials. The results will be used to inform the future development of the SPIRIT and CONSORT extensions on environmental outcomes (SPIRIT-ICE and CONSORT-ICE).

This protocol outlines the methodology for a scoping review, which will be conducted in two distinct sections: (1) identifying any existing guidelines, reviews or methodological studies describing environmental impacts of interventions and (2) identifying how environmental outcomes are reported in randomised trial protocols and trial results. A search specialist will search major medical databases, reference lists of trial publications and clinical trial registries to identify relevant publications. Data from the included studies will be extracted independently by two review authors. Based on the results, a preliminary list of items for the SPIRIT and CONSORT extensions will be developed.

This study does not include any human participants, and ethics approval is not required according to the Declaration of Helsinki. The findings from the scoping review will be published in international peer-reviewed journals, and the findings will be used to inform the design of a Delphi survey of relevant stakeholders.

Registered with Open Science 28 of February 2025.

The WHO has declared climate change the defining public health challenge of the 21st century. Incorporating climate and environmental outcomes in randomised trials is essential for enhancing healthcare treatments’ sustainability and safeguarding global health. To implement such outcomes, it is necessary to establish a framework for unbiased and transparent planning and reporting. We aim to develop extensions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT 2025) and Consolidated Standards of Reporting Trials (CONSORT 2025) statements by introducing guidelines for reporting climate and environmental outcomes.

This is a protocol for SPIRIT and CONSORT extensions on reporting climate and environmental outcomes in randomised trials termed SPIRIT-Implementing Climate and Environmental (ICE) and CONSORT-ICE. The development of the extensions will consist of five phases: phase 1—project launch, phase 2—review of the literature, phase 3—Delphi survey, phase 4—consensus meeting and phase 5—dissemination and implementation. The phases are expected to overlap. The SPIRIT-ICE and CONSORT-ICE extensions will be developed in parallel. The extensions will guide researchers on how and what to report when assessing climate and environmental outcomes.

The protocol was submitted to the Danish Research Ethics Committees, Denmark in June 2025. Ethics approval is expected in September 2025. The SPIRIT and CONSORT extensions will be published in international peer-reviewed journals.

The gig economy is a promising arena to reduce unemployment and provide other benefits such as the opportunity to earn supplemental income. Like all other forms of work, the gig space also presents occupational health issues for those working in it. This proposed review is aimed at identifying and describing the common occupational health outcomes reported within this workforce; second, to examine the risk factors that contribute to the development of these health issues; and third, to assess the interventions and support systems currently in place to promote the occupational health of gig workers.

A systematic review will be undertaken according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (2009). A search from 2015 to 2025 will be conducted on four global databases (Web of Science, SCOPUS, Academic Source Complete and Business Source Complete). Only records in English, full text and peer-reviewed journal articles will be included. Book chapters, thesis, reports and systematic reviews will be excluded. The Joanna Briggs Institute Critical Appraisal Tools will be used to assess the methodological rigour of various studies prior to inclusion for the final analysis. The extracted data will be synthesised using a narrative synthesis approach, integrating findings from both quantitative and qualitative studies.

This research is exempt from ethics approval because the work will be carried out on published documents. We will disseminate this protocol in a related peer-reviewed journal.

CRD420250654059.

Paediatric hospitalisation, encompassing the period from admission to discharge, often involves feelings of pain, fear and anxiety, primarily due to clinical diagnoses and, more significantly, discomfort and stress-inducing procedures. Numerous methodologies and interventions have been investigated and implemented to alleviate these phenomena during paediatric hospitalisation. Virtual reality (VR), for example, has demonstrated efficacy in pain relief for hospitalised children in recent studies. This systematic review, therefore, aims to identify and evaluate the effectiveness of VR in alleviating pain, fear and anxiety in hospitalised children undergoing painful procedures.

This systematic review and meta-analysis will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols guidelines. A systematic search will be conducted in March and April 2025 across the following databases, with no restrictions on language or publication year: PubMed, Embase, Scopus, Web of Science, Cumulated Index in Nursing and Allied Health Literature, ClinicalTrials.gov and the Cochrane Central Register of Controlled Trials. Eligible studies will include randomised and quasi-randomised clinical trials involving children (aged 2–10 years) and adolescents (aged 10–18 years) who received VR interventions during painful procedures. Data will be managed and analysed using Review Manager software (RevMan 5.2.3). In cases of significant heterogeneity (I² > 50%), a random-effects model will be employed to combine studies and calculate the OR with a 95% CI. The methodological quality of the included studies will be assessed using the Cochrane Risk of Bias 2.0 tool, and the certainty of the evidence will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluations framework.

This study will solely review published data; thus, ethical approval is not required. This systematic review is expected to provide subsidies, evidence and insights into the use of VR. It is also anticipated that the results will directly impact the improvement of care for these patients and the qualification of professional care.

CRD42024568297.

Acute pain in the postoperative period of cardiac surgery is mostly treated with opioid analgesics. However, with the risk of adverse reactions and complications, strategies which do not involve opioid analgesics can be considered, such as aromatherapy. This systematic review aims to analyse the effectiveness of aromatherapy in relieving pain in post-cardiac surgery patients.

Two researchers will independently and simultaneously conduct searches and select studies from the following databases: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Latin American and Caribbean Literature on Health Sciences, Scopus, Web of Science, Cochrane (Library) and clinical trial registries (clinicaltrials.com), with no language or publication date restrictions. Randomised and quasi-randomised clinical trials on the use of aromatherapy for pain relief in postcardiac surgery patients will be included. Then, two researchers will independently examine the studies based on inclusion criteria, extract data from the included studies and assess the risk of bias using the Risk of Bias 2 tool and the Risk of Bias in Non-randomized Studies of Interventions tool from Cochrane. Data will be synthesised using Review Manager software. The strength of the evidence will be evaluated using the Grading of Recommendation Assessment, Development and Evaluation approach. The literature search, study selection, review and meta-analysis stages will be conducted from early October 2025 to April 2026.

This study is based on secondary data, and therefore ethical approval from a research ethics committee was not required. The results will be disseminated through publication in a peer-reviewed scientific journal.

CRD42024568532.

The evidence for the optimal duration of psychotherapy for borderline personality disorder (BPD) is scarce. Two previous trials have compared different durations of psychotherapy. The first compared 6 months versus 12 months of dialectical behaviour therapy for BPD (the FASTER trial). The second compared 5 months versus 14 months of mentalisation-based therapy for BPD (the MBT-RCT trial). The primary objective of the present study will be to provide an individual patient data pooled analysis of two randomised clinical trials by combining the two short-term groups and the two long-term groups from the FASTER and MBT-RCT trials, thereby providing greater statistical power than the individual trials. Accordingly, we will evaluate the overall evidence on the effects of short-term versus long-term psychotherapy for BPD and investigate whether certain subgroups might benefit from short-term versus long-term psychotherapy.

An individual patient data pooled analysis of the FASTER trial and the MBT-RCT trial will be conducted. The primary outcome will be a composite of the proportion of participants with a suicide, a suicide attempt or a psychiatric hospitalisation. The secondary outcome will be the proportion of participants with self-harm. Exploratory outcomes will be BPD symptoms, symptom distress, level of functioning and quality of life. We will primarily assess outcomes at 15 months after randomisation for the FASTER trial and at 16 months after randomisation for the MBT-RCT trial. Predefined subgroups based on the design variables in the original trials will be tested for interaction with the intervention as follows: trial, sex (male compared with female), age (below or at 30 years compared with above 30 years) and baseline level of functioning (Global Assessment of Functioning baseline score at 0–49 compared with 50–100).

The statistical analyses will be performed on anonymised trial data that have already been approved by the respective ethical committees that originally assessed the included trials. The final analysis will be published in a peer-reviewed scientific journal and the results will be presented at national seminars and international conferences.

CRD42024612840.

Asthma is a leading cause of morbidity and healthcare use among children. Risk factors of childhood asthma include atopic predisposition and severe wheezing episodes caused by rhinovirus infection in early life. In children with first-time rhinovirus-induced wheezing, we aim to study the response of a short corticosteroid treatment to prevent recurrent wheezing and asthma.

This is a double-blind, randomised, placebo-controlled, phase IV, international multicentre trial involving eight sites in Norway, Sweden and Finland. Two hundred and eighty 3–23 months old steroid-naïve children are randomised 1:1 to receive oral dexamethasone (0.3 mg/kg/day) versus placebo in 3 days for their first wheezing episode and rhinovirus infection. Rhinovirus is diagnosed with multiplex PCR. The two co-primary outcomes are time to next physician-confirmed wheezing episode, and time to asthma, within 24 months from inclusion. Asthma is defined as fulfilment of the 2007 National Asthma Education and Prevention Program—criteria for initiating asthma controller medication in children aged 0–4 years. Primary interaction analyses are age, gender, atopic predisposition, risk genotypes and viral co-detection. The optimal cut-off on the rhinovirus genome load used to define a true rhinovirus infection will be assessed by exploring interactions between rhinovirus genomic loads and study drug on the co-primary outcomes. Secondary outcomes are number of wheezing episodes, duration and severity of each wheezing episode, bronchial hyperreactivity, quality of life and safety (height/weight development) at 24 months from inclusion.

Rhinovirus positive children with acute wheezing fulfilling inclusion and exclusion criteria are enrolled after informed consent from both caregivers. This trial has received ethical approval from all sites. Results will be submitted to Competent Authorities and disseminated via peer-reviewed publications and conferences within paediatrics and other relevant fields. If proven effective, findings may be implemented directly into paediatric clinical guidelines.

NCT03889743.

Time-lapse imaging (TLI) systems for embryo incubation and assessment are hypothesised to improve the success rates of in vitro fertilisation (IVF) treatment by providing undisturbed culture conditions for embryos and/or providing more information on embryo development (morphokinetic parameters) to improve predictive accuracy for embryo selection. Despite numerous aggregate meta-analyses showing uncertainty of benefit, IVF clinics globally continue to invest significant resources into this technology with little translation of evidence into guidelines or policy frameworks. This may be attributed to heterogeneity in participant populations and/or variations in the use of TLI, as highlighted in the aggregate meta-analyses.

Our research proposal for evidence synthesis using individual participant data meta-analysis will provide greater power than aggregate meta-analysis to detect differential treatment effects for effectiveness (live birth, clinical pregnancy) and safety (pregnancy loss, multiple births, congenital malformations) outcomes across three comparisons (overall effect, undisturbed culture and morphokinetic parameters). We will also analyse if there are specific subgroups of women who may benefit from the intervention and if variations in use of the intervention show any benefits. We have incorporated the results of the literature search used for the latest Cochrane review (7 January 2019) into this review and will include all the trials included therein. We will further update the literature search to include new evidence by searching the electronic databases MEDLINE, EMBASE, CINAHL and CENTRAL from 07/01/2019 to date, outcomes for all ongoing trials reported in the 2019 Cochrane review, trial registers for newer ongoing/completed trials and the citation lists of all the newly identified trials for any relevant references. The search strategy will include a combination of subject headings and text words relating to or describing the participants and the intervention, with no language restrictions. Two authors will independently screen the titles and abstracts, and full text of articles retrieved from the search, to finalise a list of trials suitable for inclusion in the review. We will include randomised controlled trials that assess TLI systems for either undisturbed culture and/or use of morphokinetic parameters for embryo selection in women having IVF/ICSI treatment using their own oocytes.

Ethical approval is not required for this study. We plan to disseminate the findings of the research to all stakeholders, including the National Institute for Health and Care Excellence and other international guideline development groups, through publication in peer-reviewed journals, presentation at conferences, newsletters, meetings and websites of the funders, fertility charities and patient support groups.

CRD42024564332.

Post-traumatic stress disorder (PTSD) constitutes a significant anxiety disorder that exerts substantial societal and familial impacts, while concurrently imposing an additional as well as a substantial burden on the healthcare system. Beyond the direct expenses incurred in its treatment, PTSD also gives rise to broader economic costs. The details of these costs in the UK are currently, we believe, unknown.

Our methodology was developed collaboratively with a collaborative advisory group of clinicians, patients, carers and other stakeholders. A comprehensive search strategy was devised to identify articles, including systematic reviews evaluating the economic costs linked to PTSD. We adhered to the National Institute for Health and Care Excellence checklist for economic evaluations. After applying our search strategy, the selected included papers were analysed to identify various cost categories contributing to the economic burden of PTSD.

PubMed, PsycInfo, PTSDpubs, EMBASE and Google Scholar were searched from January 1990 until January 2023; the search was revised and re-run in September 2024.

The articles must have been published originally in English and include a detailed evaluation of costs related to PTSD.

Two independent reviewers used standardised methods to search, screen and code included papers. After applying our search strategy, selected included papers were analysed to identify various cost categories contributing to the economic burden of PTSD. Detailed information on per-contact and per-session costs of healthcare variables was obtained at 2020/2021 prices. Additionally, with the advisory group, we ensured the validity of frequencies and unit cost figures associated with variables linked to PTSD. Further, indirect socio-economic costs arising from PTSD were computed.

By extrapolating from cost components identified, our findings indicate an average annual cost exceeding £14 780 per person. Given current 2020/2021 prevalence rates, this translates to an annual societal burden of £40 billion, a figure that does not encompass the many additional financial burdens stemming from PTSD, such as poor or inconsistent employment. This figure does not include the myriad intangible costs ranging from reduced quality of life to suicidality and countless other issues a person may suffer from as a result of PTSD. Finally, this number does not capture the breadth of impact, as it is difficult to quantify how the families, communities and social systems are adversely affected (both financially and otherwise) by the condition.

The economic and societal burden of PTSD in the UK is far greater than what extant research and common understanding indicate, as there is minimal awareness and information relating to indirect costs or ancillary effects such as discrimination, joblessness, substance use and other comorbidities. Ultimately, we found that there exists, conservatively, an annual excess societal burden of £40 billion, or approximately £14 780 per person. We demonstrated that PTSD is a significantly larger burden on society and individuals than estimated and that we are gravely underquantifying the cost of this increasingly prevalent condition.

Sarcopenia, osteoporosis and osteosarcopenia are conditions prevalent in ageing that impair muscle strength and bone density, increasing the risks of fractures, falls, disability and mortality. Recent studies highlight the benefits of milk protein supplementation (MPS) combined with exercises to improve musculoskeletal health in the older population. This systematic review protocol will enable the production of a compilation of evidence that will elucidate the effects of MPS combined with aerobic exercise, resistance exercise or both on the musculoskeletal function of older individuals with these three conditions.

Studies will be selected from electronic databases, including PubMed/MEDLINE, EMBASE, Scopus, Web of Science and the Cochrane Library, without restrictions on language or publication date. The outcomes evaluated will include muscle mass, muscle strength, BMD and physical performance after combined interventions of MPS and physical exercise of any type. The risk of bias will be assessed using the Cochrane Risk of Bias 2 tool. The Grading of Recommendations Assessment, Development and Evaluation approach will be used to classify the certainty of the evidence into four levels: high, moderate, low and very low. Meta-analysis will be performed given the homogeneity of the studies, using random effects methods in the face of the expected heterogeneity. The standardised mean difference (SMD) will be used for continuous data, and the I² index will assess heterogeneity (I² > 50%). Sensitivity analysis, ‘leave one out’ and a strategy for dealing with missing data will be carried out. Statistical analysis will be conducted using the STATA 18 software with a 95% CI and p

Formal ethical approval will not be required as primary data collection will not be performed. The results will be disseminated through peer-reviewed publications and presentations at conferences dedicated to the relevant field of study.

CRD42024555933.

Mental health problems are important causes of disability and economic costs worldwide. Randomised clinical trials examining the treatment of mental health disorders measure heterogeneous outcomes, causing difficulties in data synthesis, interpretation and translation into clinical practice. The aim of the Patient Important Outcomes in Psychiatry (PIO-Psych) Initiative is to develop an overarching, transdiagnostic research-based and consensus-based core outcome set for adult mental health disorders.

The development of the PIO-Psych transdiagnostic core outcome set will include three phases: (1) a systematic scoping review of the literature to develop the initial list of outcomes for the Delphi study; (2) a Delphi study in three rounds including people with lived experience of mental health disorders and their relatives, clinicians, researchers and others (administrators, mental healthcare policymakers, philosophers); (3) a hybrid consensus meeting to agree on the final overarching, transdiagnostic core outcome set and corresponding time points of assessment of each outcome.

Ethical approval is not applicable to this study according to the Research Ethics Committee of the Capital Region of Denmark, as it is not an interventional study. All data will be reported anonymously, and it will not be possible to identify study participants. Results will be disseminated via stakeholder and research networks and peer-reviewed publications.

The PIO-Psych Initiative was pre-registered with COMET (Core Outcome Measures for Effectiveness Trials) on 17 May 2024 (https://www.comet-initiative.org/Studies/Details/3125).

Molar incisor hypomineralisation (MIH) is a qualitative developmental defect of the enamel with a complex, multifactorial nature and a significant genetic component. Individuals with MIH have a compromised stomatognathic system manifested by muscle hyperactivity under postural and dynamic conditions. However, there is a gap in knowledge on the specific functional abnormalities that these individuals experience. Early identification and intervention, with a focus on the prevention of orofacial dysfunctions and deviations in facial growth and development, are aspects of the utmost importance. Therefore, the aim of the proposed study is to perform a comparative analysis of orofacial functions with an emphasis on breathing and chewing patterns in individuals with and without MIH. The secondary objective is to assess whether dentin hypersensitivity and the severity of MIH lesions are associated with alterations in orofacial functions.

Assessments will be performed using the Nordic Orofacial Test-Screening (NOT-S). Descriptive analyses will characterise the sample. The Shapiro-Wilk test will assess normality. For normally distributed data, analysis of variance and Tukey’s post hoc test will be used. For non-normal data, the Mann-Whitney U test will be applied. The 2 test will analyse categorical variables and compare NOT-S domains between groups. Potential confounders (eg, age, sex, socioeconomic status) will be controlled through stratification or as covariates. Logistic and Poisson regressions will model associations for categorical and count-based outcomes, respectively. Statistical significance will be set at p

This protocol has been approved by the Human Research Ethics Committee of Nove de Julho University (certificate number: 83969924.2.0000.5511; approval date: 22 November 2024). Participants will agree to take part in the study by signing an informed consent form. The findings will be published in a peer-reviewed journal. The collected data will be available on request.

NCT06692257.

The AMBulatoRy blOod preSsure In older Adults (AMBROSIA) study cohort was designed to determine whether ambulatory blood pressure (BP) monitoring (ABPM) is useful for identifying older adults with hypertension taking antihypertensive medication who are at increased risk for falls. The association of home BP monitoring (HBPM) with falls was assessed in an ancillary study (AMBROSIA-HOME).

AMBROSIA was a prospective observational study of adults aged 65 years and older taking antihypertensive medication for hypertension. Participants were recruited from Kaiser Permanente Southern California (KPSC), an integrated healthcare delivery system, and enrolled from May 2019 to November 2022. Demographic and clinical characteristics and geriatric assessments were collected over the course of two consecutive study visits. Participants completed a 24-hour ABPM and 1 week of HBPM. Over the following year, falls were assessed using a monthly falls calendar, and serious fall injuries were assessed from the KPSC electronic health record (EHR).

We enrolled 670 participants; 656 completed 24-hour ABPM and 536 also completed HBPM. The mean (SD) age of the AMBROSIA cohort was 75 (6) years, 16% were over 80 years of age and 56% were female. There were 13% non-Hispanic Asian or Pacific Islander, 22% non-Hispanic Black, 18% Hispanic and 44% non-Hispanic White participants. Nearly 72% had mild cognitive impairment, 50% were pre-frail and 4% were frail. Overall, 87% of participants returned all monthly calendars during follow-up.

The AMBROSIA cohort can be updated with longitudinal data from the EHR including antihypertensive medication to explore the relationship of fall risk and white coat effect, defined as the difference between clinic BP and out-of-clinic BP, BP variability over 24 hours and postprandial BP decline with antihypertensive medication intensification during follow-up. Additionally, the cohort can be updated to include outcomes data from the EHR such as cardiovascular events to examine BP phenotypes as potential predictors of cardiovascular events.

Cardiovascular diseases remain the leading cause of mortality worldwide. Tirzepatide is approved for the treatment of type 2 diabetes mellitus and overweight and is increasingly used. The adverse effects with tirzepatide may not be disease-specific and have not been assessed previously.

We will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index—Science (CPCI-S)) and clinical trial registries from their inception and onwards to identify relevant randomised clinical trials. We expect to conduct the literature search in January 2025. Two review authors will independently extract data and perform risk of bias assessments. We will include randomised clinical trials comparing tirzepatide versus placebo or no intervention in all patient groups with an increased risk of cardiovascular events. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be myocardial infarction, stroke, all-cause hospitalisation and non-serious adverse events. Data will be synthesised by meta-analyses and Trial Sequential Analysis, risk of bias will be assessed with the Cochrane Risk of Bias tool—version 2. We will systematically assess if the thresholds for statistical and clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations.

This protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals.

CRD42024599035.

The opioid crisis is a significant burden on adolescent public health in the USA. Medical use of prescription opioids is a pathway via which adolescents transition to opioid misuse, opioid use disorder and overdose. More than half of all opioids prescribed to adolescents are for pain management following surgery. Yet, little is known about the critical period following surgery during which adolescents initiate opioid misuse or the modifiable mechanisms (such as sleep deficiency) contributing to this process. This prospective observational study will broaden our knowledge by examining associations between sleep deficiency and opioid use and misuse following surgery. We will also examine behavioural, psychological, family and social factors linking sleep deficiency with opioid use and misuse.

Adolescents (10–19 years) undergoing outpatient orthopaedic surgery, along with one parent, will be recruited from two paediatric hospitals, for a sample of 400 dyads. Adolescents will be assessed at six timepoints. Before surgery, participants will undergo comprehensive multimodal sleep assessments (sleep surveys and actigraphy). Participants will also report on previous substance use, pain intensity and psychosocial, family and social factors. Adolescents will then be closely monitored over the first 14 days following surgery using ecological momentary assessment methods to capture real-time, naturalistic, daily data on sleep, opioid use, pain and psychological factors (including mood, affect and subjective response to opioid use). Opioid use (total number of doses and duration) will be measured with an innovative electronic medication monitoring device following surgery. Follow-up assessments at 3 months, 6 months, 12 months and 24 months will track the development of opioid misuse over time. Our primary outcomes include opioid use during the immediate 14 days following surgery and the presence of opioid misuse at 24 months after surgery. Multilevel mediation models will determine associations between predictor variables and acute postsurgical opioid use. We will apply modern machine learning algorithms to develop and validate models predicting adolescent prescription opioid misuse at 24 months from surgery.

This study was approved by Advarra’s Center for Institutional Review Board Intelligence (CIRBI) (Protocol 00072049), which serves as the single IRB of record for this multisite study.