The safety of digital mental health interventions: Systematic review and recommendations

Background: Evidence suggests that digital mental health interventions (DMHIs) for common mental health conditions are effective. However, digital interventions, such as face-to-face therapies, pose risks to patients. A safe intervention is considered one in which the measured benefits outweigh the identified and mitigated risks. Objective: This study aims to review the literature to assess how DMHIs assess safety, what risks are reported, and how they are mitigated in both the research and postmarket phases and building on existing recommendations for assessing, reporting, and mitigating safety in the DMHI and standardizing practice. Methods: PsycINFO, Embase, and MEDLINE databases were searched for studies that addressed the safety of DMHIs. The inclusion criteria were any study that addressed the safety of a clinical DMHI, even if not as a main outcome, in an adult population, and in English. As the outcome data were mainly qualitative in nature, a meta-analysis was not possible, and qualitative analysis was used to collate the results. Quantitative results were synthesized in the form of tables and percentages. To illustrate the use of a single common safety metric across studies, we calculated odds ratios and CIs, wherever possible. Results: Overall, 23 studies were included in this review. Although many of the included studies assessed safety by actively collecting adverse event (AE) data, over one-third (8/23, 35%) did not assess or collect any safety data. The methods and frequency of safety data collection varied widely, and very few studies have performed formal statistical analyses. The main treatment-related reported AE was symptom deterioration. The main method used to mitigate risk was exclusion of high-risk groups. A secondary web-based search found that 6 DMHIs were available for users or patients to use (postmarket phase), all of which used indications and contraindications to mitigate risk, although there was no evidence of ongoing safety review. Conclusions: The findings of this review show the need for a standardized classification of AEs, a standardized method for assessing AEs to statically analyze AE data, and evidence-based practices for mitigating risk in DMHIs, both in the research and postmarket phases. This review produced 7 specific, measurable, and achievable recommendations with the potential to have an immediate impact on the field, which were implemented across ongoing and future research. Improving the quality of DMHI safety data will allow meaningful assessment of the safety of DMHIs and confidence in whether the benefits of a new DMHI outweigh its risks

Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40–45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC50 for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 lM compared to 28.1 and 19.2 lM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml-1, like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3–6.6 mg were shown to be well tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83–1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2–0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity

Mechanisms and in vivo functions of contact inhibition of locomotion

Contact inhibition of locomotion (CIL) is a process whereby a cell ceases motility or changes its trajectory upon collision with another cell. CIL was initially characterized more than half a century ago and became a widely studied model system to understand how cells migrate and dynamically interact. Although CIL fell from interest for several decades, the scientific community has recently rediscovered this process. We are now beginning to understand the precise steps of this complex behaviour and to elucidate its regulatory components, including receptors, polarity proteins and cytoskeletal elements. Furthermore, this process is no longer just in vitro phenomenology; we now know from several different in vivo models that CIL is essential for embryogenesis and in governing behaviours such as cell dispersion, boundary formation and collective cell migration. In addition, changes in CIL responses have been associated with other physiological processes, such as cancer cell dissemination during metastasis

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator

Background The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). Methods The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. Findings Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. Interpretation The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. Funding Work supported by Wellcome/EPSRC Centre for Medical Engineering,King’s Together Fund and Oxford University