The Tools for Integrated Management of Childhood Illness (TIMCI) study protocol: a multi-country mixed-method evaluation of pulse oximetry and clinical decision support algorithms.

Effective and sustainable strategies are needed to address the burden of preventable deaths among children under-five in resource-constrained settings. The Tools for Integrated Management of Childhood Illness (TIMCI) project aims to support healthcare providers to identify and manage severe illness, whilst promoting resource stewardship, by introducing pulse oximetry and clinical decision support algorithms (CDSAs) to primary care facilities in India, Kenya, Senegal and Tanzania. Health impact is assessed through: a pragmatic parallel group, superiority cluster randomised controlled trial (RCT), with primary care facilities randomly allocated (1:1) in India to pulse oximetry or control, and (1:1:1) in Tanzania to pulse oximetry plus CDSA, pulse oximetry, or control; and through a quasi-experimental pre-post study in Kenya and Senegal. Devices are implemented with guidance and training, mentorship, and community engagement. Sociodemographic and clinical data are collected from caregivers and records of enrolled sick children aged 0-59 months at study facilities, with phone follow-up on Day 7 (and Day 28 in the RCT). The primary outcomes assessed for the RCT are severe complications (mortality and secondary hospitalisations) by Day 7 and primary hospitalisations (within 24 hours and with referral); and, for the pre-post study, referrals and antibiotic. Secondary outcomes on other aspects of health status, hypoxaemia, referral, follow-up and antimicrobial prescription are also evaluated. In all countries, embedded mixed-method studies further evaluate the effects of the intervention on care and care processes, implementation, cost and cost-effectiveness. Pilot and baseline studies started mid-2021, RCT and post-intervention mid-2022, with anticipated completion mid-2023 and first results late-2023. Study approval has been granted by all relevant institutional review boards, national and WHO ethical review committees. Findings will be shared with communities, healthcare providers, Ministries of Health and other local, national and international stakeholders to facilitate evidence-based decision-making on scale-up.Study registration: NCT04910750 and NCT05065320.

Pulse oximetry and clinical decision support algorithms show potential for supporting healthcare providers to identify and manage severe illness among children under-five attending primary care in resource-constrained settings, whilst promoting resource stewardship but scale-up has been hampered by evidence gaps.This study design article describes the largest scale evaluation of these interventions to date, the results of which will inform country- and global-level policy and planning .

Operational Differences between Product Development Partnership, Pharmaceutical Industry, and Investigator Initiated Clinical Trials.

Medicine development is a lengthy endeavour. Increasing regulatory stringency and trial complexity might lead to reduced efficiency, dwindled output, and elevated costs. However, alternative models are possible. We compared the operational differences between pharmaceutical industry sponsored trials, product development partnership trials, and investigator-initiated trials to identify key drivers of inefficiency in clinical research. We conducted an exploratory mixed-methods study with stakeholders, including clinical trial sponsors, contract research organisations, and investigators. The qualitative component included 40 semi-structured interviews, document reviews of 12 studies and observations through work shadowing in research institutions in Burkina Faso, Mali, and Switzerland. The findings were triangulated with an online survey polling clinical research professionals. The operational differences were grouped under five categories: (i) trial start-up differences including governance and management structure; (ii) study complexity; (iii) site structural and organisational differences; (iv) study conduct, quality approaches, and standard operating procedures; and (v) site capacity strengthening and collaboration. Early involvement of sites in the planning and tailored quality approaches were considered critical for clinical operations performance. Differences between the types of trials reviewed pertained to planning, operational complexities, quality approaches, and support to the sites. Integration of quality-by-design components has the potential to alleviate unnecessary process burden.

Key Contributions by the Swiss Tropical and Public Health Institute Towards New and Better Drugs for Tropical Diseases.

Thanks to its expertise in clinical research, epidemiology, infectious diseases, microbiology, parasitology, public health, translational research and tropical medicine, coupled with deeply rooted partnerships with institutions in low- and middle-income countries (LMICs), the Swiss Tropical and Public Health Institute (Swiss TPH) has been a key contributor in many drug research and development consortia involving academia, pharma and product development partnerships. Our know-how of the maintenance of parasites and their life-cycles in the laboratory, plus our strong ties to research centres and disease control programme managers in LMICs with access to field sites and laboratories, have enabled systems for drug efficacy testing in vitro and in vivo, clinical research, and modelling to support the experimental approaches. Thus, Swiss TPH has made fundamental contributions towards the development of new drugs - and the better use of old drugs - for neglected tropical diseases and infectious diseases of poverty, such as Buruli ulcer, Chagas disease, food-borne trematodiasis (e.g. clonorchiasis, fascioliasis and opisthorchiasis), human African trypanosomiasis, leishmaniasis, malaria, schistosomiasis, soil-transmitted helminthiasis and tuberculosis. In this article, we show case the success stories of molecules to which Swiss TPH has made a substantial contribution regarding their use as anti-infective compounds with the ultimate aim to improve people's health and well-being.

Opportunities and challenges for decentralised clinical trials in sub-Saharan Africa: a qualitative study.

INTRODUCTION: Digital health has gained traction in research and development, and clinical decision support systems. The COVID-19 pandemic accelerated the adoption of decentralised clinical trials (DCTs) as a mitigation and efficiency improvement strategy. We assessed the opportunities and challenges of a digital transformation in clinical research in sub-Saharan Africa from different stakeholders' perspectives. METHODS: A qualitative study, including 40 in-depth semi structured interviews, was conducted with investigators of three leading research institutions in sub-Saharan Africa and Switzerland, contract research organisations and sponsors managing clinical trials in sub-Saharan Africa. A thematic approach was used for the analysis. RESULTS: Interviewees perceived DCTs as an opportunity for trial efficiency improvement, quality improvement and reducing the burden of people participating in clinical trials. However, to gain and maintain an optimal quality of clinical trials, a transition period is necessary to tackle contextual challenges before DCTs are being implemented. The main challenges are categorised into four themes: (1) usability and practicability of the technology; (2) paradigm shift and trial data quality; (3) ethical and regulatory hurdles and (4) contextual factors (site-specific research environment and sociocultural aspects). CONCLUSION: The transformation from a site to a patient-centric model with an increased responsibility of participants should be context adapted. The transformation requires substantial investment, training of the various stakeholders and an efficient communication. Additionally, commitment of sponsors, investigators, ethics and regulatory authorities and the buy-in of the communities are essential for this change.

Determining the Spike-Wave Index Using Automated Detection Software.

PURPOSE: The spike-wave index (SWI) is a key feature in the diagnosis of electrical status epilepticus during slow-wave sleep. Estimating the SWI manually is time-consuming and is subject to interrater and intrarater variability. Use of automated detection software would save time. Thereby, this software will consistently detect a certain EEG phenomenon as epileptiform and is not influenced by human factors. To determine noninferiority in calculating the SWI, we compared the performance of a commercially available spike detection algorithm (P13 software, Persyst Development Corporation, San Diego, CA) with human expert consensus. METHODS: The authors identified all prolonged EEG recordings for the diagnosis or follow-up of electrical status epilepticus during slow-wave sleep carried out from January to December 2018 at an epilepsy tertiary referral center. The SWI during the first 10 minutes of sleep was estimated by consensus of two human experts. This was compared with the SWI calculated by the automated spike detection algorithm using the three available sensitivity settings: "low," "medium," and "high." In the software, these sensitivity settings are denoted as perception values. RESULTS: Forty-eight EEG recordings from 44 individuals were analyzed. The SWIs estimated by human experts did not differ from the SWIs calculated by the automated spike detection algorithm in the "low" perception mode (P = 0.67). The SWIs calculated in the "medium" and "high" perception settings were, however, significantly higher than the human expert estimated SWIs (both P < 0.001). CONCLUSIONS: Automated spike detection (P13) is a useful tool in determining SWI, especially when using the "low" sensitivity setting. Using such automated detection tools may save time, especially when reviewing larger epochs.

Using sampled visual EEG review in combination with automated detection software at the EMU.

PURPOSE: Complete visual review of prolonged video-EEG recordings at an EMU (Epilepsy Monitoring Unit) is time consuming and can cause problems in times of paucity of educated personnel. In this study we aimed to show non inferiority for electroclinical diagnosis using sampled review in combination with EEG analysis softreferware (P13 software, Persyst Corporation), in comparison to complete visual review. METHOD: Fifty prolonged video-EEG recordings in adults were prospectively evaluated using sampled visual EEG review in combination with automated detection software of the complete EEG record. Visually assessed samples consisted of one hour during wakefulness, one hour during sleep, half an hour of wakefulness after wake-up and all clinical events marked by the individual and/or nurses. The final electro-clinical diagnosis of this new review approach was compared with the electro-clinical diagnosis after complete visual review as presently used. RESULTS: The electro-clinical diagnosis based on sampled visual review combined with automated detection software did not differ from the diagnosis based on complete visual review. Furthermore, the detection software was able to detect all records containing epileptiform abnormalities and epileptic seizures. CONCLUSION: Sampled visual review in combination with automated detection using Persyst 13 is non-inferior to complete visual review for electroclinical diagnosis of prolonged video-EEG at an EMU setting, which makes this approach promising.