Epidemiology of ambulance utilized patients in Addis Ababa, Ethiopia

Background Well organized and appropriately utilized pre-hospital emergency services play a critical role in augmenting emergency care systems. The primary objective of this study was to understand the demographic and clinical profile of patients who used ambulances in Addis Ababa. The secondary objectives were to assess ambulance response time, transport time and reasons for referral amongst inter-facility transported patients in Addis Ababa. Methods The study was designed as a cross-sectional retrospective chart review of ambulance transported patients using ambulance station records from Addis Ababa Fire and Emergency Prevention and Control Authority. With IRB approval, simple random sampling and manual review of six months of clinical records was performed. Data were collected by trained data collectors and descriptive analysis was done using SPSS version 20. Results Female patients used ambulance services more often than males (female to male ratio of 3:1) and the mean age of the patients was 26 years. The most commonly transported age group was 16–30 years, followed by 31–50 years and neonatal patients (i.e. < 1 month). The majority of the patients had pregnancy related illnesses (n = 492, 61.4%), followed by general medical issues (n = 210, 26.2%) and injury secondary to trauma (n = 99, 12.3%). Most patients (n = 702, 87.6%) were transported for inter-facility transfers, while only 12.4% (n = 99) were primary responses (i.e. from the scene). Prolonged labor was the most common reason (n = 103, 23.4%) for inter-facility transfer of pregnant patients, followed by premature rupture of the amniotic membrane (n = 60, 13.6%). The mean dispatch to scene time interval was 10.1 min, and mean scene to facility time interval was 17.2 min. Conclusion Inter-facility transfers accounted for the largest proportion of ambulance utilization and dispatch in Addis Ababa. Ambulance transport time was twice as long compared to international recommendations of less than eight minutes for emergent transports. The most common reasons for ambulance dispatch were Obstetric. We recommend urgent action to decrease the transport times and to dedicate further pre-hospital resources to address the high burden of inter-facility transfers

The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS): study protocol for a randomised controlled, experimental medicine study

Abstract Background The discovery that voltage-gated calcium channel genes such as CACNA1C are part of the aetiology of psychiatric disorders has rekindled interest in the therapeutic potential of L-type calcium channel (LTCC) antagonists. These drugs, licensed to treat hypertension and angina, have previously been used in bipolar disorder, but without clear results. Neither is much known about the broader effects of these drugs on the brain and behaviour. Methods The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS) is a high-intensity randomised, double-blind, placebo-controlled experimental medicine study on the effect of the LTCC antagonist nicardipine in healthy young adults with mood instability. An array of cognitive, psychiatric, circadian, physiological, biochemical and neuroimaging (functional magnetic resonance imaging and magnetoencephalography) parameters are measured during a 4-week period, with randomisation to drug or placebo on day 14. We are interested in whether nicardipine affects the stability of these measures, as well as its overall effects. Participants are genotyped for the CACNA1C risk polymorphism rs1006737. Discussion The results will clarify the potential of LTCC antagonists for repurposing or modification for use in psychiatric disorders in which cognition, mood and sleep are affected. Trial registration ISRCTN, ISRCTN33631053. Retrospectively registered on 8 June 2018 (applied 17 May 2018)

Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of childbearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or nonlinear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1 week to 1 month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1 day to 2 weeks and a variable bioavailability of 30–82 %. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215 L/day and 3.60–5.29 L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20–79 %) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into pharmacokinetic/pharmacodynamic models to enable individualized dosing in real time

A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer

Abstract Background Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. Methods We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. Results A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. Conclusions Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME