Designing e-consent protocols for pragmatic clinical trials: case studies from a UKCRC clinical trials unit.

BACKGROUND: Interest in and use of electronic consent (e-consent) in the conduct of academic clinical trials has increased since the COVID-19 pandemic. E-consent offers advantages including increased efficiency and accessibility, and reduced burden on site staff, which can be appealing to academic trialists anticipating challenges in recruitment to complex trial designs or with limited funding. However, there are many options to consider when using e-consent in a study protocol. This paper presents five case studies from Norwich Clinical Trials Unit, demonstrating how e-consent models can be effectively tailored to the needs of different trials. These examples illustrate the options around and benefits of e-consent, the acceptability of e-consent by participants, and the design considerations that were made during the development of the trial protocols. CASE STUDIES: Five randomised trials are presented, selected from a range of different trial designs, disease areas, interventions, and patient populations. E-consent was either offered as an alternative to paper consent, according to participant preference, or as the sole method of consent. E-consent was generally used to facilitate remote consent in decentralised trials but was also chosen to increase efficiency and reduce burden in an emergency department setting. The technical implementation of e-consent and detailed participant procedures were tailored to the needs of the trial settings and patient populations. For example, accompanying participant information sheets were provided in paper or electronic form, and electronic signatures could be typed or drawn. Administrative data on uptake of e-consent is presented where available. CONCLUSION: This paper demonstrates that the operational and technical aspects of implementing e-consent in clinical trials can be influenced by the trial design, the needs and characteristics of the trial population, financial/efficiency considerations, and level of risk. E-consent is not a one-size-fits-all tool for trials, and its use should be carefully considered during the development of the trial protocol, in conjunction with patient and public involvement contributors, site staff and other trial stakeholders.

A phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-06939999 (PRMT5 inhibitor) in patients with selected advanced or metastatic tumors with high incidence of splicing factor gene mutations.

BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor. PATIENTS AND METHODS: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities. RESULTS: In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified. CONCLUSIONS: PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection.

Trial Forge Guidance 4: a guideline for reporting the results of randomised Studies Within A Trial (SWATs).

BACKGROUND: Evidence to support decisions on trial processes is minimal. One way to generate this evidence is to use a Study Within A Trial (SWAT) to test trial processes or explore methodological uncertainties. SWAT evidence relies on replication to ensure sufficient power and broad applicability of findings. Prompt reporting is therefore essential; however, SWAT publications are often the first to be abandoned in the face of other time pressures. Reporting guidance for embedded methodology trials does exist but is not widely used. We sought therefore to build on these guidelines to develop a straightforward, concise reporting standard, which remains adherent to the CONSORT guideline. METHODS: An iterative process was used to develop the guideline. This included initial meetings with key stakeholders, development of an initial guideline, pilot testing of draft guidelines, further iteration and pilot testing, and finalisation of the guideline. RESULTS: We developed a reporting guideline applicable to randomised SWATs, including replications of previous evaluations. The guideline follows the Consolidated Standards for Reporting Trials (CONSORT) statement and provides example text to ensure ease and clarity of reporting across all domains. CONCLUSIONS: The SWAT reporting guideline will aid authors, reviewers, and journal editors to produce and review clear, structured reports of randomised SWATs, whilst also adhering to the CONSORT guideline. TRIAL REGISTRATION: EQUATOR Network - Guidelines Under Development ( https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials/#SWAT ). Registered on 25 March 2021.

Cash outs during in-play sports betting: Who, why, and what it reveals.

Cashing out is a popular feature of modern 'in-play' sports betting that allows sports bettors to withdraw a bet before the sporting event on which the bet was placed is finalized. Previous studies have shown that use of the cash out feature is positively related to problem gambling symptomatology. However, little is known about demographic and psychological characteristics of in-play sports bettors who use the cash out feature, or their motivations for use. To fill this knowledge gap, we recruited 224 adults (18 + years) from Ontario who engaged in in-play sports betting in the past three months. Participants completed self-report measures of psychological and gambling-related variables. Participants also provided qualitative responses for their motivations for using the cash out feature. Approximately half (51.8 %) of the participants reported using the cash out feature. No statistically significant demographic differences were found between participants who used and did not use the cash out feature. Participants who used the feature (compared to those who did not) reported higher problematic alcohol and cannabis use, feelings of depression, anxiety, and stress, and were motivated to gamble to make money. The primary reasons for cashing out were to access money immediately, to cut losses, and because cashing out felt like a less risky option. The current findings shed light on underlying psychological vulnerabilities associated with individuals who use the cash out feature, which can inform initiatives to reduce the harms associated with this popular feature of sports betting.

The Room Where It Happens: Clinician Reflections on Returning Preclinical Alzheimer's Biomarker Results to Research Participants.

Disclosing Alzheimer's disease (AD) biomarkers to research participants is a growing practice. Here, we aim to synthesize the experiences of clinicians leading preclinical AD biomarker disclosure. Semi-structured interviews were conducted individually with each of the four clinicians conducting biomarker disclosure as a part of a longitudinal, observational AD cohort study. Study clinicians emphasized the importance of participant education, having adequate time available for the disclosure visit, and forms to facilitate disclosure. To train and support future clinicians conducting AD biomarker disclosure, our study clinicians highlighted providing information about AD and biomarkers, shadowing a disclosure visit, having team debriefing sessions, and collating a frequently asked questions document. To date, this is the first characterization of clinician reflections on disclosing AD biomarker result to cognitively unimpaired research participants. As more clinicians in research or clinical settings seek to disclose AD biomarker results, best practices for training clinicians to lead disclosure are necessary.

Regional tissue oxygenation in asymptomatic neonates at high risk for neonatal abstinence syndrome and impact of non-pharmacologic interventions: A case report.

BACKGROUND: Improving neonatal abstinence syndrome (NAS) management is an important concern, and objective measures of its physiologic impact remain elusive. We sought to determine whether near-infrared spectroscopy (NIRS)-derived tissue oxygenation (rSO2) and fractional tissue oxygen extraction (FTOE) demonstrated physiologically plausible changes correlating with standard NAS scoring. METHODS: Thirty subjects (mean 39 weeks' GA and 3 127 g BW) underwent cerebral and peripheral muscle NIRS monitoring on Days of Life (DOL) Three, Five, and Seven. We examined correlations between NAS scores and FTOE and assessed the impact of non-pharmacologic swaddling and cuddling. RESULTS: No statistically significant correlations between NAS scores and FTOE were observed; however, plausible trends were demonstrated between NAS scores and cerebral measurements. Buprenorphine-exposed babies (57%) showed significantly lower FTOE when swaddled (DOL7). CONCLUSIONS: Tissue oxygenation monitoring demonstrates potential to provide objective, clinically relevant physiologic information on infants at risk for NAS. Further study is required to determine whether NIRS-derived measures could assist in individualizing NAS care.

Athlete mental health help-seeking: A systematic review and meta-analysis of rates, barriers and facilitators.

Athletes are vulnerable to a range of mental health symptoms, in part due to stressors within the sport environment. An early intervention framework suggests the benefits of routine screening and referral for mental health, however, greater understanding around athlete help-seeking is needed to support referral uptake. This review examined rates of formal help-seeking behaviour as well as barriers and facilitators to help-seeking in sport settings. Relevant studies were retrieved from SportDiscus, PubMed and PsycInfo, with unpublished studies identified through contacting authors. Help-seeking rates were meta-analysed and barriers and facilitators were meta-synthesised. Twenty-two studies were included. Help-seeking rates were reported in 11 studies (N = 3415) and the pooled proportion of help-seeking was 22.4 % (95 % CI 16.2-30.2, I2 = 95.7 %). Barriers were reported in 13 studies and facilitators in six, highlighting a range of sporting-specific factors, such as stigma in relation to athlete identity and sport culture, fear of deselection, and concerns around confidentiality in sport settings, in addition to lack of awareness, low mental health literacy, and negative attitudes to services. Normalising experiences of mental health in sport settings, including through role models, was a key facilitator to help-seeking. Results provide implications for sport organisations to promote help-seeking and athlete mental health, such as through the use of role models, ensuring clarity around confidentiality, stigma reduction interventions, and fostering team cultures that promote mental health. Findings also support the value of sport staff in facilitating help-seeking, and organisational culture changes to foster wellbeing.

Ultrastructural observation of the airways of recovered and susceptible pigs after inoculation with Mycoplasma hyopneumoniae

To determine the morphological differences in the epithelium of the airways of recovered and susceptible pigs after Mycoplasma hyopneumoniae challenge, twenty-four 4-week-old M. hyopneumoniae-free pigs were intratracheally inoculated with 107ccu/ml of a pure low-passaged culture of the P5722-3 strain of M. hyopneumoniae challenge material. Eight pigs (group I) were challenged at the beginning of the experiment and rechallenged 3 months later. Group II pigs were also challenged at the beginning of the experiment and necropsied 3 months later. Group III pigs were challenged at the same time as the rechallenge of group I pigs. Eight nonchallenged pigs served as controls (group IV). Three days after the second challenge of group I and the first challenge of group III, and every 3 and 4 days thereafter, two pigs from each group were euthanatized by electrocution and necropsied. Samples of bronchi and lung tissue were examined using light and electron microscopy (SEM and TEM). Macroscopic lesions were observed in the lungs of all group III pigs (average = 4.74%) and were characterized by purple-red areas of discoloration and increased firmness affecting the cranioventral aspect of the lungs. Macroscopic lesions of pneumonia in groups I and II were minimal (less than 1%). There were no gross lesions of pneumonia in control (group IV) pigs. Microscopic lesions were characterized by hyperplasia of the peribronchial lymphoid tissue and mild neutrophilic infiltrates in alveoli. Electron microscopy showed patchy areas with loss of cilia and presence of leukocytes and mycoplasmas in bronchi of susceptible pigs (group III). The bronchial epithelium of rechallenged (group I), recovered (group II), and control (group IV) pigs was ultrastructurally similar indicating recovery of the former two groups. Although mycoplasmas were seen among cilia, a second challenge on pigs of group I did not produce another episode of the disease nor did it enhance morphological changes, suggesting that those pigs could become carriers of M. hyopneumoniae

Preliminary report on an archaeological survey in the Llanos de Mojos, Bolivia: San Ignacio to San Borja

Contiene: Estudios preliminares de arqueologia en los llanos de San Borja Bolivia