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Teresa A Simon,1 John H Simon,1 Erin G Heaning,1 Andres Gomez-Caminero,1 Jahan P Marcu1,2 1Physicians Research Center, LLC, Toms River, NJ, USA; 2Marcu Enterprises, Jersey City, NJ, USACorrespondence: Teresa A Simon, Physicians Research Center, LLC, Toms River, NJ, 08753, USA, Tel +732 818-7900, Fax +732 557-0217, Email prctrials@gmail.comPurpose: The aim of this study was to characterize the frequency of adverse effects where delta-8 tetrahydrocannabinol (D8-THC) was identified as a possible suspect drug in the FDA Adverse Event Reporting System (FAERS) database.Methods: A case-series design was used.Results: A total of 183 cases listed D8-THC as a suspect drug in FAERS as of June 30, 2021. The most common events included dyspnea, respiratory disorder, and seizure. The reporting odds ratios were consistently and significantly greater than 2, a 2-fold increase from 2019 to 2021, indicating a potential safety signal.Conclusion: The first report of D8-THC, in the FAERS database, as a suspect drug appears to be in 2011. Overall, there are 183 total cases listing D8-THC as a suspect drug in the FAERS database as of June 30, 2021. Of the 183 cases, most were respiratory in nature.Keywords: cannabis, hemp-derived, safety, adverse effects, public health, cannabinoid, delta-8 tetrahydrocannabinol, hemp, adverse event

Teresa A Simon,1 Marlene S Khouri,2 Tzuyung D Kou,3 Andres Gomez-Caminero3 1Physicians Research Center, LLC, Toms River, NJ, USA; 2Innovation Law, Bristol Myers Squibb, Princeton, NJ, USA; 3Worldwide Patient Safety, Bristol Myers Squibb, Princeton, NJ, USACorrespondence: Teresa A SimonPhysicians Research Center, LLC, Toms River, NJ 08755, USATel +1 732 818-7900Email prctrials@gmail.comAbstract: Assessing a patient’s perspective on their treatment is part of an increasingly integrated approach to pharmacovigilance and treatment optimization. New tools and methods developed in partnership with patients can capture and quantify cognitive and behavioral aspects of the treatment experience. These treatment insights have the potential to shape the drug development process, as well as supplement patient-reported outcome data in a way that is meaningful to the patient. We highlight examples of tools developed to assess the impact of treatment on the aspects of disease that are of utmost concern to the patient in their daily life.Keywords: drug development, patient engagement, patient perspective, patient-reported outcome

Abstract Background Mid-portion Achilles tendinopathy is a common condition, characterised by localised Achilles tendon load-related pain and dysfunction. Numerous non-surgical treatments have been proposed for the treatment of this condition, but many of these treatments have a poor or non-existent evidence base. Heel lifts have also been advocated as a treatment for Achilles tendinopathy, but the efficacy and mechanism of action of this intervention is unclear. This proposal describes a randomised controlled trial comparing the effectiveness of heel lifts versus sham heel lifts for reducing pain associated with mid-portion Achilles tendinopathy, with an embedded biomechanical analysis. Methods One hundred and eight men and women aged 18 to 65 years with mid-portion Achilles tendinopathy (who satisfy the inclusion and exclusion criteria) will be recruited. Participants will be randomised, using the website Sealed Envelope, to either a control group (sham heel lifts) or an experimental group (heel lifts). Both groups will be provided with education regarding acceptable pain levels to ensure all participants receive some form of treatment. The participants will be instructed to use their allocated intervention for at least 8 h every day for 12 weeks. The primary outcome measure will be pain intensity (numerical rating scale) at its worst over the previous week. The secondary outcome measures will be additional measures of Achilles tendon pain and disability, participant-perceived global ratings of change, function, level of physical activity and health-related quality of life. Data will be collected at baseline and the primary endpoint (week 12). Data will be analysed using the intention-to-treat principle. In addition, the acute kinetic and kinematic effects of the interventions will be examined at baseline in a subpopulation of the participants (n = 40) while walking and running using three-dimensional motion analysis. Discussion The LIFT trial (efficacy of heeL lIfts For mid-portion Achilles Tendinopathy) will be the first randomised trial to compare the efficacy of heel lifts to a sham intervention in reducing pain and disability in people with Achilles tendinopathy. The biomechanical analysis will provide useful insights into the mechanism of action of heel lifts. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12623000627651 . Registered 7 June 2023.

Objectives The study aims to (1) report the process of recruiting young adults into a secondary knee osteoarthritis prevention randomised controlled trial (RCT) after anterior cruciate ligament reconstruction (ACLR); (2) determine the number of individuals needed to be screened to include one participant (NNS) and (3) report baseline characteristics of randomised participants.Methods The SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER)-Knee RCT compares SUPER and minimal intervention for young adults (aged 18–40 years) with ongoing symptoms (ie, mean score of

Summary: Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious—and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia. Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5–20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2–4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority. Findings: We identified 22 randomised studies with 1350 patients reporting on serious—and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01–2.43, 17 studies, I2 = 47%). Three studies reported little or no influence on pubertal development following 2–4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations. Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Summary: Background: Melatonin prescriptions for children and adolescents have increased substantially during the last decade. Existing clinical recommendations focus on melatonin as a treatment for insomnia related to neurodevelopmental disorders. To help guide clinical decision-making, we aimed to construct a recommendation on the use of melatonin in children and adolescents aged 5–20 years with idiopathic chronic insomnia. Methods: A systematic search for guidelines, systematic reviews and randomised controlled trials (RCT) were performed in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A search for adverse events in otherwise healthy children and adolescents was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 18, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (5–20 years of age) with idiopathic chronic insomnia, in whom sleep hygiene practices have been inadequate and melatonin was tested. There were no restrictions on dosage, duration of treatment, time of consumption, or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, all-cause dropouts, and non-serious adverse events. Outcomes were assessed at different time points to assess short-term and long-term effects. Meta-analysis was performed using inverse variance random-effects model and risk of bias was assessed using Cochrane risk of bias tool. If possible, funnel plots would be constructed to investigate publication bias. Heterogeneity was calculated via I2 statistics. A multidisciplinary guideline panel formulated the recommendation according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was subsequently used to discuss the feasibility and acceptance of the constructed recommendation alongside the impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We included eight RCTs with 419 children and adolescents with idiopathic chronic insomnia. Melatonin led to a moderate increase in total sleep time by 30.33 min (95% confidence interval (CI) 18.96–41.70, 4 studies, I2 = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI −26.61 to −9.44, 3 studies, I2 = 0%), both as assessed by sleep diary. No other beneficial effects were found. None of the studies provided information on serious adverse events, yet the number of participants experiencing non-serious adverse events was increased (Relative risk 3.44, 95% CI 1.25–9.42, 4 studies, I2 = 0%). Funnel plots were not constructed due to the low number of studies. The certainty of evidence was very low on the quality of sleep and low for daytime functioning. Interpretation: Evidence of very low certainty shows that benefits are limited and unwanted events are likely when melatonin is used to treat otherwise healthy children and adolescents with chronic insomnia. Melatonin should never be the first choice of treatment for this particular population, yet carefully monitored short-term use may be considered if sleep hygiene practices and non-pharmacological interventions have proven inadequate, and only if daytime function is compromised. Funding: The Danish Health Authority and the Parker Institute, Bispebjerg and Frederiksberg Hospital supported by the Oak Foundation.

Summary: Background: Melatonin has become a widely used sleeping aid for young individuals currently not included in existing guidelines. The aim was to develop a recommendation on the use of melatonin in children and adolescents aged 2–20 years, with chronic insomnia due to disorders beyond indication. Methods: We performed a systematic search for guidelines, systematic reviews, and randomised trials (RCTs) in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A separate search for adverse events was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 17, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (2–20 years of age) with chronic insomnia due to underlying disorders, in whom sleep hygiene practices have been inadequate and melatonin was tested. Studies exclusively on autism spectrum disorders or attention deficit hyperactive disorder were excluded. There were no restrictions on dosage, duration of treatment, time of consumption or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events, assessed at 2–4 weeks post-treatment. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, non-serious adverse events, and all-cause dropouts (assessed at 2–4 weeks post-treatment), plus quality of sleep and daytime functioning (assessed at 3–6 months post-treatment). Pooled estimates were calculated using inverse variance random effects model. Statistical heterogeneity was calculated using I2 statistics. Risk of bias was assessed using Cochrane risk of bias tool. Publication bias was assessed using funnel plots. A multidisciplinary guideline panel constructed the recommendation using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was used to discuss the feasibility and acceptance of the constructed recommendation and its impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We identified 13 RCTs, including 403 patients with a wide range of conditions. Melatonin reduced sleep latency by 14.88 min (95% CI 23.42–6.34, 9 studies, I2 = 60%) and increased total sleep time by 18.97 min (95% CI 0.37–37.57, 10 studies, I2 = 57%). The funnel plot for total sleep time showed no apparent indication of publication bias. No other clinical benefits were found. The number of patients experiencing adverse events was not statistically increased however, safety data was scarce. Certainty of evidence was low. Interpretation: Low certainty evidence supports a moderate effect of melatonin in treating sleep continuity parameters in children and adolescents with chronic insomnia due to primarily medical disorders beyond indication. The off-label use of melatonin for these patients should never be the first choice of treatment, but may be considered by medical specialists with knowledge of the underlying disorder and if non-pharmacological interventions are inadequate. If treatment with melatonin is initiated, adequate follow-up to evaluate treatment effect and adverse events is essential. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Cerebrovascular disease (CVD) poses a major public health and socio-economic burden worldwide due to its high morbidity and mortality rates. Accurate assessment of cerebral arteries’ haemodynamic plays a crucial role in the diagnosis and treatment management of CVD. The study compared a non-imaging transcranial Doppler ultrasound (TCD) and transcranial color-coded Doppler ultrasound (with (cTCCD) and without (ncTCCD)) angle correction in quantifying middle cerebral arteries (MCAs) haemodynamic parameters. A cross-sectional study involving 50 healthy adults aged ≥ 18 years was conducted. The bilateral MCAs were insonated via three trans-temporal windows (TTWs—anterior, middle, and posterior) using TCD, cTCCD, and ncTCCD techniques. The MCA peak systolic velocity (PSV) and mean flow velocity (MFV) were recorded at proximal and distal imaging depths that could be visualised on TCCD with a detectable spectral waveform. A total of 152 measurements were recorded in 41 (82%) subjects with at least one-sided open TTW across the three techniques. The mean PSVs measured using TCD, ncTCCD, and cTCCD were 83 ± 18 cm/s, 81 ± 19 cm/s, and 93 ± 21 cm/s, respectively. There was no significant difference in PSV between TCD and ncTCCD (bias = 2 cm/s, p = 1.000), whereas cTCCD yielded a significantly higher PSV than TCD and ncTCCD (bias = −10 cm/s, p < 0.001; bias = −12 cm/s, p ≤ 0.001, respectively). The bias in MFV between TCD and ncTCCD techniques was (bias = −0.5 cm/s; p = 1.000), whereas cTCCD demonstrated a higher MFV compared to TCD and ncTCCD (bias = −8 cm/s, p < 0.001; bias = −8 cm/s, p ≤ 0.001, respectively). TCCD is a practically applicable imaging technique in assessing MCA blood flow velocities. cTCCD is more accurate and tends to give higher MCA blood flow velocities than non-imaging TCD and ncTCCD techniques. ncTCCD is comparable to non-imaging TCD and should be considered in clinical cases where using both TCD and TCCD measurements is needed.

Digital interventions can increase physical activity (PA) levels in adults. However, the COVID-19 pandemic highlighted the complexities faced when guiding people to start or return to PA following illness or inactivity. A digital tool, Movement Foundations, was developed to provide remote guidance on building strength and capacity across functional movement patterns, with graduated progression based on user responses and input. This qualitative study aimed to explore the perceived impacts of using the tool. Nine participants aged over 35 years from the healthcare and academic healthcare sectors were recruited to use it and were subsequently interviewed. Thematic analysis identified three themes falling under the overarching concept of ‘Capability, Opportunity and Motivation—Behaviour (COM-B) Plus’, encompassing: skills and capacity for movement; opportunities, motivations and barriers for movement; and a personalised, safe space in which to develop. Participants felt that the digital tool increased their capacity and confidence in movement and positively impacted their daily activities. External factors such as illness and stress clouded perceptions of the impacts of PA. Time, work pressures and needing equipment were still considered significant barriers to PA. Still, participants appreciated the flexibility and non-prescriptive nature of the tool and felt that it helped movement to become opportunistic and habitual. Increased capacity for PA and feeling the subsequent physical and mental effects positively influenced motivation. Structure and guidance, with graduated progress, were seen as protective. Guided self-reflection helped participants understand their capacity and limitations with regard to movement and promoted motivation. Although acquiring technical skills to guide movement may be important for those recovering from illness, participants found that a structure promoting individualised guidance, graduated progression and guided self-reflection were important motivational factors for continuing use. Digital interventions should consider these aspects when seeking to promote habitual PA.

Active surveillance (AS) has gained acceptance as a primary management approach for patients diagnosed with low-risk prostate cancer (PC). In this qualitative study, we compared perspectives between patients and health care professionals (HCP) to identify what may contribute to patient–provider discordance, influence patient decision-making, and interfere with the uptake of AS. We performed a systematic comparison of perspectives about AS reported from focus groups with men eligible for AS (7 groups, N = 52) and HCP (5 groups, N = 48) who engaged in conversations about AS with patient. We used conventional content analysis to scrutinize separately focus group transcripts and reached a consensus on similar or divergent viewpoints between them. Patients and clinicians agreed that AS was appropriate for low grade PC and understood the low-risk nature of the disease. They shared the perspective that disease status was a critical factor to pursue or discontinue AS. However, men expressed a greater emphasis on quality of life in their decisions related to AS. Patients and clinicians differed in their perspectives on the clarity, availability, and volume of information needed and offered; clinicians acknowledged variations between HCP when presenting AS, while patients were often compelled to seek additional information beyond what was provided by physicians and experienced difficulty in finding or interpreting information applicable to their situation. A greater understanding of discordant perspectives about AS between patients and HCP can help improve patient engagement and education, inform development of knowledge-based tools or aids for decision-making, and identify areas that require standardization across the clinical practice.

Abstract Background Although mesenchymal stem/stromal cell (MSC) chondrogenic differentiation has been thoroughly investigated, the rudiments for enhancing chondrogenesis have remained largely dependent on external cues. Focus to date has been on extrinsic variables such as soluble signals, culture conditions (bioreactors), and mechanical stimulation. However, the role of intrinsic mechanisms of MSC programming-based mechanobiology remains to be explored. Since aggregation of MSCs, a prerequisite for chondrogenesis, generates tension within the cell agglomerate, we inquired if the initial number of cells forming the aggregate (aggregate cell number (ACN)) can impact chondrogenesis. Methods Aggregates of varying ACN were formed using well-established centrifugation approach. Progression of chondrogenic differentiation in the aggregates was assessed over 3 weeks in presence and absence of transforming growth factor-beta 1 (TGF-β1). Mechanical properties of the cells were characterized using high-throughput real-time deformability cytometry (RT-DC), and gene expression was analyzed using Affymetrix gene array. Expression of molecular markers linked to chondrogenesis was assessed using western blot and immunofluorescence. Results Reducing ACN from 500 k to 70 k lead to activation and acceleration of the chondrogenic differentiation, independent of soluble chondro-inductive factors, which involves changes to β-catenin-dependent TCF/LEF transcriptional activity and expression of anti-apoptotic protein survivin. RT-DC analysis revealed that stiffness and size of cells within aggregates are modulated by ACN. A direct correlation between progression of chondrogenesis and emergence of stiffer cell phenotype was found. Affymetrix gene array analysis revealed a downregulation of genes associated with lipid synthesis and regulation, which could account for observed changes in cell stiffness. Immunofluorescence and western blot analysis revealed that increasing ACN upregulates the expression of lipid raft protein caveolin-1, a β-catenin binding partner, and downregulates the expression of N-cadherin. As a demonstration of the relevance of these findings in MSC-based strategies for skeletal repair, it is shown that implanting aggregates within collagenous matrix not only decreases the necessity for high cell numbers but also leads to marked improvement in the quality of the deposited tissue. Conclusions This study presents a simple and donor-independent strategy to enhance the efficiency of MSC chondrogenic differentiation and identifies changes in cell mechanics coincident with MSC chondrogenesis with potential translational applications.

Abstract Background This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia. Methods This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics. Results Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change. Conclusions Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges. Trial registration ClinicalTrials.gov, NCT01540630. EudraCT, 2010-023963-16. 07 Aug 2015.