Community case management and referral of children with fever within the primary health care system in Uganda.

Malaria remains a leading cause of under-five childhood morbidity and mortality in Sub- Saharan Africa and a third of febrile children lack prompt access to effective malaria case management services. Community health workers (CHW) provide an opportunity to deliver malaria diagnosis and treatment in primary health care settings closer to populations at risk. Recognising the potential of CHWs, many malaria endemic countries have national CHW programmes to provide case management services for malaria and other common childhood infections. However, for children that present to CHWs with signs and symptoms they are unable to manage current CHW guidelines indicate referral to the nearest health centre. Despite the scale-up of CHW programmes, there is little understanding of the referral processes and this thesis aimed to examine the processes as part of malaria case management trials with CHWs conducted in Rukungiri District, Uganda. The referral process was explored in four objectives that mirrored a child’s continuum of care beginning at the CHW and ending at the public health centre. The first objective assessed CHWs adherence to the referral guidelines; the second examined the effect of CHWs using malaria rapid diagnostic tests (mRDT) on referrals; and the third examined caregiver’s compliance to referral advice. Finally, the fourth objective described changes in outpatient department (OPD) visits and case-mix at health facilities over a 24- month period, before and after the start of the trials. The referral study was carried out as part of two cluster randomised trials which assessed the impact of CHWs using mRDTs on appropriate treatment of malaria when compared to presumptive diagnosis. Secondary analyses of routine CHW records revealed that two-thirds of children eligible for referral were not referred, including children with severe malaria. Although, the use of mRDTs improved the odds of referral compared to presumptive diagnoses, almost 90% of caregivers failed to comply with CHW referral advice which was associated with factors such as distance from health facilities, seasonality and treatment seeking during the weekend. Compared to the pre-trial period, OPD visits at health facilities declined and case-mix changed following the start of the trial. Overall these findings show the referral processes can be monitored using routinely available data using appropriate indicators. Changes in the number and type of visits seen at health facilities, indicate that health resources could be allocated differently. Most importantly, these data show that the referral process intended to ensure the care of children with referral signs and symptoms did not perform well. Referral is key component of primary health care and the process requires strengthening to ensure a continuum of care in community case management settings. New interventions should be developed involving CHWs, caregivers and health facilities to overcome the referral barriers and consequently improve CHWs adherence to referral guidelines as well as caregivers compliance to referral advice

Co-infection with Onchocerca volvulus and Loa loa microfilariae in central Cameroon: are these two species interacting?

Ivermectin treatment may induce severe adverse reactions in some individuals heavily infected with Loa loa. This hampers the implementation of mass ivermectin treatment against onchocerciasis in areas where Onchocerca volvulus and L. loa are co-endemic. In order to identify factors, including co-infections, which may explain the presence of high L. loa microfilaraemia in some individuals, we analysed data collected in 19 villages of central Cameroon. Two standardized skin snips and 30 mul of blood were obtained from each of 3190 participants and the microfilarial (mf) loads of both O. volvulus and L. loa were quantified. The data were analysed using multivariate hierarchical models. Individual-level variables were: age, sex, mf presence, and mf load; village-related variables included the endemicity levels for each infection. The two species show a certain degree of ecological separation in the study area. However, for a given individual host, the presence of microfilariae of one species was positively associated with the presence of microfilariae of the other (OR=1.79, 95% CI [1.43-2.24]). Among individuals harbouring Loa microfilariae, there was a slight positive relationship between the L. loa and O. volvulus mf loads which corresponded to an 11% increase in L. loa mf load per 100 O. volvulus microfilariae. Co-infection with O. volvulus is not sufficient to explain the very high L. loa mf loads harboured by some individuals

Cryopreservation of human mesenchymal stromal cells expressing TRAIL for human anti-cancer therapy

Background aims Mesenchymal stromal cells (MSCs) are being extensively researched for cell therapy and tissue engineering. We have engineered MSCs to express the pro-apoptotic protein tumor necrosis factor–related apoptosis inducing ligand (TRAIL) and are currently preparing this genetically modified cell therapy for a phase 1/2a clinical trial in patients with metastatic lung cancer. To do this, we need to prepare a cryopreserved allogeneic MSCTRAIL cell bank for further expansion before patient delivery. The effects of cryopreservation on a genetically modified cell therapy product have not been clearly determined. Methods We tested different concentrations of dimethyl sulfoxide (DMSO) added to the human serum albumin ZENALB 4.5 and measured post-thaw cell viability, proliferation ability and differentiation characteristics. In addition, we examined the homing ability, TRAIL expression and cancer cell–killing capacities of cryopreserved genetically modified MSCs compared with fresh, continually cultured cells. Results We demonstrated that the post-thaw viability of MSCs in 5% DMSO (v/v) with 95% ZENALB 4.5 (v/v) is 85.7 ± 0.4%, which is comparable to that in conventional freezing media. We show that cryopreservation does not affect the long-term expression of TRAIL and that cryopreserved TRAIL-expressing MSCs exhibit similar levels of homing and, importantly, retain their potency in triggering cancer cell death. Conclusions This study shows that cryopreservation is unlikely to affect the therapeutic properties of MSCTRAIL and supports the generation of a cryopreserved master cell bank

Fully quantum state-resolved inelastic scattering of NO(X) + Kr: Differential cross sections and product rotational alignment

Fully quantum state selected and resolved inelastic scattering of NO(X) by krypton has been investigated. Initial Λ-doublet state selection is achieved using an inhomogeneous hexapole electric field. Differential cross sections and even-moment polarization dependent differential cross sections have been obtained at a collision energy of 514 cm^−1 for both spin-orbit and parity conserving and changing collisions. Experimental results are compared with those obtained from quantum scattering calculations and are shown to be in very good agreement. Hard shell quantum scattering calculations are also performed to determine the effects of the different parts of the potential on the scattering dynamics. Comparisons are also made with the NO(X)+Ar system

The novel ECF56 SigG1-RsfG system modulates morphological differentiation and metal-ion homeostasis in Streptomyces tsukubaensis

Extracytoplasmic function (ECF) sigma factors are key transcriptional regulators that prokaryotes have evolved to respond to environmental challenges. Streptomyces tsukubaensis harbours 42 ECFs to reprogram stress-responsive gene expression. Among them, SigG1 features a minimal conserved ECF s2–s4 architecture and an additional C-terminal extension that encodes a SnoaL_2 domain, which is characteristic for ECF s factors of group ECF56. Although proteins with such domain organisation are widely found among Actinobacteria, the functional role of ECFs with a fused SnoaL_2 domain remains unknown. Our results show that in addition to predicted self-regulatory intramolecular amino acid interactions between the SnoaL_2 domain and the ECF core, SigG1 activity is controlled by the cognate anti-sigma protein RsfG, encoded by a co-transcribed sigG1-neighbouring gene. Characterisation of ¿sigG1 and ¿rsfG strains combined with RNA-seq and ChIP-seq experiments, suggests the involvement of SigG1 in the morphological differentiation programme of S. tsukubaensis. SigG1 regulates the expression of alanine dehydrogenase, ald and the WhiB-like regulator, wblC required for differentiation, in addition to iron and copper trafficking systems. Overall, our work establishes a model in which the activity of a s factor of group ECF56, regulates morphogenesis and metal-ions homeostasis during development to ensure the timely progression of multicellular differentiation.This work was partially funded by National Funds through FCT-Fundação para a Ciência e a Tecnologia, I.P., under the project ERA-IB-2/0001/2015. It was further supported by FEDER - Fundo Europeu de Desen-volvimento Regional funds through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020; and by Portuguese funds through FCT Fundação para a Ciência e a Tecnologia, I.P/Ministério da Ciência, Tecnologia e Ensino Superior POCI-01-0145-FEDER-007274 and NORTE-01-0145-FEDER-000012. BBSRC supported this work through the Institute Strategic Programme grant BB/J004561/1 to the John Innes Centre. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. R.O. was supported by the FCT fellowship SFRH/ BD/107862/2015 and by the EMBO fellowship ASTF438-2015, M.V.M. was supported by the FCT fellowship SFRH/BPD/95683/2013 and the FCT contract DL57/2016/CP1355/CT0023 and D.C.P. and G.F. were supported through the IMPRS-Mic and the ERASynBio project ECFexpress (BMBF grant 031L0010B). The authors are grateful to Kim Findlay at the Bioimaging platform of the John Innes Centre (JIC, UK) for performing the SEM imaging of S. tsukubaensis samples, Mervyn Bibb (JIC, UK) for the pIJ12333 plasmid , Mark Buttner (JIC, UK) for his comments and discussion regarding the work and Paula Tamagnini (i3S, PT) for comments on the manuscript. The authors acknowledge the support of the i3S Scientific Platforms Cell Culture and Genotyping, Biochemical and Biophysical Technologies and Proteomics

Fichte and Hegel on Recognition

In this paper I provide an interpretation of Hegel’s account of ‘recognition’ (Anerkennung) in the 1802-3 System of Ethical Life as a critique of Fichte’s account of recognition in the 1796-7 Foundations of Natural Right. In the first three sections of the paper I argue that Fichte’s account of recognition in the domain of right is not concerned with recognition as a moral attitude. I then turn, in section four, to a discussion of Hegel’s critique and transformation of Fichte’s conception of recognition. Hegel’s transformation consists, I argue, in the claim that a comprehensive account of recognition in the domain of right must be concerned with recognition as a moral attitude

Neighbourhood, Route and Workplace-Related Environmental Characteristics Predict Adults' Mode of Travel to Work

Commuting provides opportunities for regular physical activity which can reduce the risk of chronic disease. Commuters' mode of travel may be shaped by their environment, but understanding of which specific environmental characteristics are most important and might form targets for intervention is limited. This study investigated associations between mode choice and a range of objectively assessed environmental characteristics.Participants in the Commuting and Health in Cambridge study reported where they lived and worked, their usual mode of travel to work and a variety of socio-demographic characteristics. Using geographic information system (GIS) software, 30 exposure variables were produced capturing characteristics of areas around participants' homes and workplaces and their shortest modelled routes to work. Associations between usual mode of travel to work and personal and environmental characteristics were investigated using multinomial logistic regression.Of the 1124 respondents, 50% reported cycling or walking as their usual mode of travel to work. In adjusted analyses, home-work distance was strongly associated with mode choice, particularly for walking. Lower odds of walking or cycling rather than driving were associated with a less frequent bus service (highest versus lowest tertile: walking OR 0.61 [95% CI 0.20–1.85]; cycling OR 0.43 [95% CI 0.23–0.83]), low street connectivity (OR 0.22, [0.07–0.67]; OR 0.48 [0.26–0.90]) and free car parking at work (OR 0.24 [0.10–0.59]; OR 0.55 [0.32–0.95]). Participants were less likely to cycle if they had access to fewer destinations (leisure facilities, shops and schools) close to work (OR 0.36 [0.21–0.62]) and a railway station further from home (OR 0.53 [0.30–0.93]). Covariates strongly predicted travel mode (pseudo r-squared 0.74).Potentially modifiable environmental characteristics, including workplace car parking, street connectivity and access to public transport, are associated with travel mode choice, and could be addressed as part of transport policy and infrastructural interventions to promote active commuting

High prevalence of albuminuria amongst people who inject drugs: A cross-sectional study.

Albuminuria is a key biomarker for cardiovascular disease and chronic kidney disease. Our study aimed to describe the prevalence of albuminuria amongst people who inject drugs in London and to test any potential associations with demographic characteristics, past diagnoses, and drug preparation and administration practices. We carried out a cross-sectional survey amongst people who use drugs in London. The main outcome measure was any albuminuria including both microalbuminuria and macroalbuminuria. Three-hundred and sixteen samples were tested by local laboratory services. Our study initially employed point-of-care testing methods but this resulted in a high number of false positives. Our findings suggest the prevalence of albuminuria amongst PWID is twice that of the general population at 19% (95%CI 15.3-24.0%). Risk factors associated with albuminuria were HIV (aOR 4.11 [95% CI 1.37-12.38]); followed by overuse of acidifier for dissolving brown heroin prior to injection (aOR 2.10 [95% CI 1.04-4.22]). Albuminuria is high amongst people who inject drugs compared to the general population suggesting the presence of increased cardiovascular and renal pathologies. This is the first study to demonstrate an association with acidifier overuse. Dehydration may be common amongst this population and may affect the diagnostic accuracy of point-of-care testing for albuminuria

Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations