Development and implementation experience of a learning healthcare system for facility based newborn care in low resource settings: The Neotree.

Introduction: Improving peri- and postnatal facility-based care in low-resource settings (LRS) could save over 6000 babies' lives per day. Most of the annual 2.4 million neonatal deaths and 2 million stillbirths occur in healthcare facilities in LRS and are preventable through the implementation of cost-effective, simple, evidence-based interventions. However, their implementation is challenging in healthcare systems where one in four babies admitted to neonatal units die. In high-resource settings healthcare systems strengthening is increasingly delivered via learning healthcare systems to optimise care quality, but this approach is rare in LRS. Methods: Since 2014 we have worked in Bangladesh, Malawi, Zimbabwe, and the UK to co-develop and pilot the Neotree system: an android application with accompanying data visualisation, linkage, and export. Its low-cost hardware and state-of-the-art software are used to support healthcare professionals to improve postnatal care at the bedside and to provide insights into population health trends. Here we summarise the formative conceptualisation, development, and preliminary implementation experience of the Neotree. Results: Data thus far from ~18 000 babies, 400 healthcare professionals in four hospitals (two in Zimbabwe, two in Malawi) show high acceptability, feasibility, usability, and improvements in healthcare professionals' ability to deliver newborn care. The data also highlight gaps in knowledge in newborn care and quality improvement. Implementation has been resilient and informative during external crises, for example, coronavirus disease 2019 (COVID-19) pandemic. We have demonstrated evidence of improvements in clinical care and use of data for Quality Improvement (QI) projects. Conclusion: Human-centred digital development of a QI system for newborn care has demonstrated the potential of a sustainable learning healthcare system to improve newborn care and outcomes in LRS. Pilot implementation evaluation is ongoing in three of the four aforementioned hospitals (two in Zimbabwe and one in Malawi) and a larger scale clinical cost effectiveness trial is planned.

Randomised clinical trial: efficacy and safety of the live biotherapeutic product MRx1234 in patients with irritable bowel syndrome.

BACKGROUND: MRx1234 is a live biotherapeutic product that contains a strain of Blautia hydrogenotrophica. It is in development for the treatment of irritable bowel syndrome (IBS). AIMS: To assess the efficacy and safety of MRx1234 in patients with IBS with predominant constipation (IBS-C) or diarrhoea (IBS-D) METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients aged 18-70 years in two parallel cohorts (IBS-C; IBS-D) were randomised (1:1) to MRx1234 or placebo for 8 weeks. The primary efficacy endpoint was overall responder rate-a composite of improved bowel habit (IBS-C: stool frequency; IBS-D: stool consistency) and abdominal pain intensity-for ≥50% of the treatment period in each cohort. Statistical testing was at a one-sided 0.10 significance level. RESULTS: Of 366 randomised patients (164 IBS-C; 202 IBS-D), 365 received any study medication (177 MRx1234, 188 placebo). Numerically, although not statistically significantly different, more patients who received MRx1234 than placebo were overall responders in the IBS-C (25.0% vs. 17.1%) and IBS-D (23.4% vs. 17.8%) cohorts. Similar results were observed in the additional combined cohort analysis (24.1% vs. 17.5%; p = 0.063). For the components of the primary endpoint, significantly more patients on MRx1234 than placebo reported improvement in bowel habit in the IBS-C, IBS-D and combined cohorts, while improvements in abdominal pain were observed in each cohort. The safety profile of MRx1234 was similar to placebo. CONCLUSIONS: MRx1234 has the potential to become a novel, safe treatment option for patients with IBS-C or IBS-D, and for those who have mixed symptoms or transition between subtypes. CLINICALTRIALS: gov #NCT03721107.

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation.

Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.

Oxygen management among infants in neonatal units in sub-Saharan Africa: a cross-sectional survey.

OBJECTIVES: To provide more comprehensive data on the management of oxygen supplementation in neonates in sub-Saharan Africa. STUDY DESIGN: An online survey on the management of oxygen supplementation for infants in neonatal units was sent to 278 healthcare personnel in sub-Saharan Africa. RESULTS: One hundred and nine responses from 82 neonatal care units in 54% (26/48) sub-Saharan African countries were received. All units had the capacity to provide oxygen supplementation. However, only 50% (38/76) had access to blend oxygen with medical air and 1% (1/75) had the capacity to blend oxygen/air for every infant. Although 96% (72/75) of units could monitor oxygen saturation, monitoring was mostly intermittent and only 32% (24/75) were able to monitor oxygen saturation in every infant receiving oxygen supplementation. CONCLUSIONS: Findings indicate that oxygen supplementation is inadequately managed in neonatal units in sub-Saharan Africa, which may put infants at risk of developing severe ROP.

The impact of COVID-19 on cardiology training.

The coronavirus disease 2019 (COVID-19) pandemic has produced a dramatic shift in how we practise medicine, with changes in working patterns, clinical commitments and training. Cardiology trainees in the UK have experienced a significant loss in training opportunities due to the loss of specialist outpatient clinics and reduction in procedural work, with those on subspecialty fellowships perhaps losing out the most. Training days, courses and conferences have also been cancelled or postponed. Many trainees have been redeployed during the crisis, and routes of career progression have been greatly affected, prompting concerns about extensions in training time, along with effects on mental health. With the pandemic ongoing and its effects on training likely long-lasting, we examine areas for improvement and opportunities for change in preparation for the 'new normal', including how other specialties have adapted. The increasingly routine use of video conferencing and online education has been a rare positive of the pandemic, and simulation will play a larger role. A more coordinated, national approach will need to be introduced to ensure curriculum components are covered and trainees around the country have equal access to ensure cardiology training in the UK remains world class.

Hydroxychloroquine use in COVID-19: is the risk of cardiovascular toxicity justified?

The outbreak of COVID-19 in Wuhan, China and its declaration as a global pandemic by WHO has left the medical community under significant pressure to rapidly identify effective therapeutic and preventative strategies. Chloroquine (CQ) and its analogue hydroxychloroquine (HCQ) were found to be efficacious against SARS-CoV-2 when investigated in preliminary in vitro experiments. Reports of success in early clinical studies were widely publicised by news outlets, politicians and on social media. These results led several countries to approve the use of these drugs for the treatment of patients with COVID-19. Despite having reasonable safety profiles in the treatment of malaria and certain autoimmune conditions, both drugs are known to have potential cardiotoxic side effects. There is a high incidence of myocardial injury and arrhythmia reported with COVID-19 infection, and as such this population may be more susceptible to this side-effect profile. Studies to date have now demonstrated that in patients with COVID-19, these drugs are associated with significant QTc prolongation, as well as reports of ventricular arrhythmias. Furthermore, subsequent studies have failed to demonstrate clinical benefit from either drug. Indeed, clinical trials have also been stopped early due to safety concerns over HCQ. There is an urgent need for credible solutions to the global pandemic, but we argue that in the absence of high-quality evidence, there needs to be greater caution over the routine use or authorisation of drugs for which efficacy and safety is unproven.

The role of the family doctor in the management of adults who are obese: a scoping review protocol.

BACKGROUND: The role of family doctors in the management of obesity in primary care will become increasingly important as more of the adult population become overweight or obese. Having a solid understanding of the family doctor's role as a sole practitioner is important for supporting practitioners in providing patient care and for informing future research. OBJECTIVE: The purpose of this paper is to describe a protocol for a scoping review that aims to examine and map the current research base for the role of the family doctor in managing adults who are overweight or obese. METHODS: This scoping review is based on the methodology as described by the Joanna Briggs Institute which involves final consultation with stakeholders. Two reviewers (ES, NE) will be responsible for the iterative development of a search strategy based on the basic initial search terms obesity, doctor and primary care. Black and grey literature will be searched to elucidate any manuscripts involving the family doctor in the management of adults who are overweight or obese. A customised data extraction tool will be used to collect relevant items from each manuscript. RESULTS: Data extraction will expose the role family doctors are playing in obesity management in all stages of research including recruitment, intervention or as a control group. By looking at a broad scope of manuscripts we will discover the family doctor's role as portrayed in research, in international guidelines and by peak bodies. We will also determine if there are any gaps in the research base. CONCLUSION: This protocol describes a scoping review that will illustrate the supporting international research for the role family doctors are playing in the management of adults who are overweight or obese. Scoping of the international literature will then be translated for Australian primary care.

Decatenation checkpoint-defective melanomas are dependent on PI3K for survival.

Melanoma cell lines are commonly defective for the G2-phase cell cycle checkpoint that responds to incomplete catenation of the replicated chromosomes. Here, we demonstrate that melanomas defective for this checkpoint response are less sensitive to genotoxic stress, suggesting that the defective cell lines compensated for the checkpoint loss by increasing their ability to cope with DNA damage. We performed an siRNA kinome screen to identify kinases responsible and identified PI3K pathway components. Checkpoint-defective cell lines were three-fold more sensitive to small molecule inhibitors of PI3K. The PI3K inhibitor PF-05212384 promoted apoptosis in the checkpoint-defective lines, and the increased sensitivity to PI3K inhibition correlated with increased levels of activated Akt. This work demonstrates that increased PI3K pathway activation is a necessary adaption for the continued viability of melanomas with a defective decatenation checkpoint.