Introduction: Improving health systems requires good governance alongside technical interventions. Evidence suggests that strengthening governance results in more responsive health systems. Despite receiving increased attention, governance is still a relatively new area of health systems and policy research. There is no universally agreed way to define, measure or assess health system governance. Little information exists regarding governance at sub-national (health policy implementation) level. Assessing governance at different health system levels (national, county and health facility) in Kenya is the aim of this study. The specific research objectives explored are: 1) factors influencing health system governance in Kenya; 2) key stakeholders’ perspectives on health system governance and 3) whether the status of health system governance differs with the functionality of health facilities. Methods: The study employed qualitative research methods, interviews with 39 key informants from three levels of the Kenya health system. The study used a conceptual framework adapted from previously published tools for assessing governance and draws on “institutional analysis” theory to help analyse and interpret the findings. Findings: Key factors that influence governance in the health system include devolution, rapidly changing political context, constrained health financing and challenges in managing the health workforce. The most notable influence appeared to be the impact of devolution and frequent health workers’ strikes. Stakeholders shared their views on all six principles of governance and these revealed opportunities for abuse of the system, weak enforcement of policies and accountability measures, and a lack of participation in policy development. They also commented on the lack of improvement in equity in the health system. Careful analysis using the new institutional economics theory showed that there were observed differences in governance at facility level: fully functional versus not fully functional. The most surprising difference was that staff responding to the lack or weakness of formal institutions by creating informal arrangements that might circumvent or support the goals of the formal system. Fully functional facilities had accountability mechanisms that they self-enforced; by contrast, facilities that were not fully functional lacked both self-enforcement and effective third party enforcement mechanisms. Norms and practices for controlling corruption were clear in fully functional facilities but confused in some not fully functional facilities. Conclusions: This study provides an in-depth exploration of what factors influence institutional arrangements for good governance and how these were enforced or not. Analysis guided by theory, with a strong emphasis on context, is an important contribution to the existing literature on governance. This study critically evaluated existing frameworks to assess health system governance from a cross-disciplinary perspective which can inform future research on governance. The findings highlight research implications for Kenya at policy and operational levels particularly, on the need to monitor health system governance over time due to rapidly changing political and socioeconomic circumstances, especially concurrent devolution.

No description available.

Background: For every woman who dies during pregnancy and childbirth, many more suffer ill-health, the burden of which is highest in low- and middle-income countries. The PhD study sought to assess the extent and type of maternal morbidity in these settings. Methods: A descriptive observational cross-sectional study was conducted to assess physical (infectious and medical/obstetric), psychological and social morbidity. Socio-demographic factors, education, socioeconomic status, reported symptoms, clinical examination and laboratory investigations, quality of life, and satisfaction with health were assessed. Relationships between morbidity and maternal characteristics were investigated using logistic regression analysis. Findings: 11454 women were assessed in India (2099), Malawi (2923), Kenya (3145), and Pakistan (3287). Almost 3 out of 4 women had ≥1 symptom (73.5%), abnormalities on clinical examination (71.3%) or laboratory investigation (73.5%). In total, 9.0% of women had an identified infectious disease (HIV, malaria, syphilis or chest infection) and 23.1% had signs of early sepsis with an identifiable source of infection in 43%. HIV positive status was highest in Malawi (14.5%) as was malaria (10.4%). Overall, 47.9% of women were anaemic, 11.5% had other medical or obstetric conditions, 25.1% psychological and 36.6% social morbidity. Infectious morbidity was highest in Malawi (40.5%) and Kenya (38.5%), psychological and social morbidity was highest in Pakistan (47.3%, 60.2%). Morbidity was not limited to a core at risk group; only 1.2% had a combination of all four morbidities. Age, socioeconomic status, educational, previous pregnancies, and adverse maternal or neonatal outcomes were associated with different types of morbidity per country, but there was no consistent direction of strength of association. For each country, women with medical/obstetric morbidity was more likely to report psychological and infectious morbidity, apart from Malawi. Women with an infectious morbidity were more likely to report medical/obstetric, psychological and social morbidity in Pakistan and Malawi. Women with psychological morbidity were more likely to report social morbidity in Pakistan and Kenya. Conclusion: Despite women reporting that they have a good quality of life and are satisfied with their health, there is evidence of a significant burden of infectious, medical/obstetric, psychological, and social morbidity in women during and after pregnancy. At present available antenatal and postnatal care packages do not include comprehensive screening for all forms of ill-health. This study demonstrates that women have health needs, beyond simply the physical aspects of health and includes psychological and social well-being. To ensure all women have the right to the highest attainable standard of health and well-being, current antenatal and postnatal care packages need to be adapted and improved to provide comprehensive, holistic care in a way that meets a woman’s health needs.

No description available.

Gambian human African trypanosomiasis (gHAT) is a deadly disease caused by Trypanosoma brucei gambiense transmitted by tsetse flies (Glossina) and is found only in West and Central Africa. The NW of Uganda has been known as a focus of gHAT since the early 20th Century but the number of new cases has reduced from 948 in 2000 to 4 in 2015. NW Uganda is therefore a good testing ground for alternative control and surveillance strategies that could be employed at other foci in the drive towards elimination. Focussing on the Koboko foci of gHAT in NW Uganda, this study aimed to: (i) assess the prevalence of T. b. gambiense in the vector and potential reservoir host animals (cattle and pigs), (ii) develop a system for xenomonitoring gHAT and (iii) assess the impact of Tiny-Targets, a novel vector control technology, on the transmission of salivarian trypanosomes amongst local cattle. The tsetse population was sampled continuously from April 2013-July 2014 using pyramidal traps (four traps operated on average 18 days/month). A total number of 12,532 G. f. fuscipes were captured. A subset of these tsetse (6,664) were analysed for the presence of trypanosomes using either microscopy and/or molecular methods. No tsetse tested were found to be positive for T. b. gambiense but T. brucei s.l. (2%), T. vivax (3%) and T. congolense (4%) were detected. PCR-based analyses of bloodfed tsetse (131) showed that the predominant hosts were humans (37%), cattle (39%) and Monitor lizards (15%). A xenomonitoring system based on commercially available loop-mediated isothermal amplification (LAMP) kits were tested for their suitability to detect T. brucei s.l. DNA in tsetse. The study demonstrated that the LAMP kits were highly sensitive, being able to detect the equivalent of 0.1 trypanosome/mL. They could also detect T. brucei s.l. DNA in tsetse midguts six days-post ingestion. Analyses of 2,877 cattle from areas where Tiny Targets were present or absent using microscopy and PCR-based methods found that the targets had no significant impact on trypanosome prevalence; prevalence of Trypanosoma spp in cattle from areas with or without targets was 10% for both sites. T. b. gambiense was not detected unequivocally in cattle or pigs. This study showed that in a setting where gHAT is close to elimination it is extremely difficuIt to detect the parasite in the vector population. It also indicates that local cattle and pigs are not likely to be playing a role as reservoir hosts. The commercially available LAMP kits offer the basis of a novel and more cost-effective system for monitoring T. brucei parasites in low-prevalence settings.

Insecticide-based vector control strategies have greatly contributed to malaria control, yet their success is hindered by the spread of resistance. It is thus essential to discover the molecular basis of resistance to use the current insecticides effectively and to search for new ones informatively. In Anopheles gambiae, overexpression of single detoxifying enzymes of the P450 (CYP) family has been strongly associated with resistance, yet in vivo analysis has only been performed in the fruit fly. Furthermore, patterns of P450 overexpression that lead to resistance, which are crucial to identify detoxification pathways, remain unclear. This study aims to investigate the role of two genes, Cyp6m2 and Cyp6p3, in conferring resistance in vivo in An. gambiae when overexpressed tissue-specifically in the midgut, oenocytes, or Malpighian tubules or in multiple tissues. To obtain spatially-controlled gene overexpression the GAL4/UAS system was employed. Responder lines for the expression of Cyp6s were created by PhiC31-RMCE and crossed with two tissue-specific drivers specific for the midgut or the oenocytes. Resistance phenotype assessment, conducted according to WHO guidelines, revealed no difference in mortality between mosquitoes overexpressing Cyp6 genes and controls after exposure to four different insecticides, suggesting that overexpression confined to these tissues is not sufficient to drive resistance. We therefore aimed to examine overexpression in the Malpighian tubules and in multiple tissues. Since promoters for these locations had not been characterised, putative regulatory regions were isolated from genes showing desired patterns of expression. Two main candidates, PUBc and GPI, were chosen after assessing their activity by luciferase assay in mosquito cells, and were used to create driver lines using the piggyBac transposon. Random insertion was chosen to identify single genomic sites able to sustain widespread expression and at the same time create new PhiC31 docking lines at these permissive sites. Patterns of expression induced by PUBc drivers carrying single insertions were investigated by crossing with a responder UAS:mCherry line. Two drivers were isolated that induced multi-tissue expression in all life stages and both sexes at relatively higher (A10) and lower (A8) levels. In similar experiments, the ubiquitous GPI and the Malpighian-specific VATG candidate promoters did not show visible mCherry expression. The PUBc driver lines were finally used to assess resistance resulting from multi-tissue overexpression. Ubiquitous expression of Cyp6m2 under the control of the A10 driver correlated with acquisition of WHO levels of resistance to pyrethroids, while that of Cyp6p3 with resistance to pyrethroids and bendiocarb; DDT resistance was not affected. Lower levels of overexpression driven by A8 did not significantly alter the resistance phenotype except for permethrin resistance when Cyp6m2 is overexpressed. Furthermore, Cyp6 overexpression driven by A10 or A8 caused an increase in susceptibility to the pro-insecticide malathion, supporting the role of specific CYP6s in providing negative cross-resistance between insecticide classes. This study provides the first in vivo evidence of the role of Cyp6s in causing WHO-defined resistance in An. gambiae, suggesting that location and level of overexpression are critical. Overall, this work contributed to the optimisation of a system for in vivo functional analysis in transgenic An. gambiae through the characterisation of a novel ubiquitous promoter and the ability to modulate level of expression using alternative drivers. Such a system is physiologically more relevant than the current Drosophila-based system for in vivo validation of mosquito resistance gene. In addition, metabolically resistant lines created here can be included alongside field-caught populations for screening new insecticides.

Introduction: Lower Respiratory Tract Infection (LRTI) and pneumonia are leading causes of death in the UK and costly health problems to the NHS. The aetiological pathogen is rarely found making targeted therapy difficult, hospital bed pressures are growing year on year and our current vaccinations are sub-optimal. Key questions: Current UK priorities include 1) Better diagnostics - without knowing the causal pathogen we cannot treat our patients effectively nor determine what pathogen to develop better vaccines against. Could nasal samples from hospitalised patients with LRTI/pneumonia be useful in aetiological diagnosis? 2) Better therapeutics - acute hospital bed pressures and hospital acquired infections rates are increasing. Could hospitalised patients with LRTI/pneumonia be discharged home sooner by support and treatment in the community from an early supported discharge scheme (ESDS)? 3) Better prevention - current pneumonia vaccines are inadequate. Could a new experimental model in humans using live pneumococcal bacteria help us to select from candidate pneumococcal vaccines? Main findings: We found that prior antibiotic treatment meant that nasal sampling in hospitalised patients was not useful. ESDS is safe and reduces the total hospital bed days with high rates of patient and carer/next of kin satisfaction. A large recruitment effort is needed. Using our Experimental Human Pneumococcal Carriage (EHPC) model confirmed that the current pneumococcal vaccine reduces rates of pneumococcal acquisition and carriage density. Implications: A community based study of nasal sampling techniques in patients with LRTI/pneumonia prior to antibiotic therapy may be useful. An ESDS is worthwhile but needs better integration within well-established CCG-funded chronic obstructive pulmonary disease (COPD) schemes to form a 'Respiratory ESDS' and a national multi-site RCT trial. Our robust EHPC model can now be used to test novel candidate vaccines using a smaller sample size and shorter timescales than clinical community studies in order to reduce cost and time to market.

Hematophagous insects ingest several times their body weight with each blood meal, obtaining nutrients needed for reproduction and survival in addition to high levels of free heme. However, they survive the high toxicity imposed by free heme due to the development of heme detoxification mechanisms such as heme degradation by the enzyme heme oxygenase (HOs). Despite being present in several disease vector insects, including tsetse flies that transmit sleeping sickness, the role and biochemical features of HOs in blood feeding insects is poorly studied. Here, we have cloned and expressed HO from the tsetse fly Glossina morsitans morsitans to determine whether the enzyme was active, unveil its biochemical features and develop specific antibodies to investigate HO distribution in this insect. HPLC analysis of midgut contents from G. m. morsitans was performed to track the degradation of heme and conversion to biliverdin during the first 6 days following a single blood meal, showing that whilst heme concentration roses to 3 mM at 48 hours after a single blood meal, the maximum concentration reached by biliverdin is 0.5 μM after 96 hours, suggesting that despite HO being active in the insect, it may play a minor role in heme degradation. Comparison of recombinant HOs suggests that the heme oxygenase from G. m.morsitans (GmmHO) degrades heme slower and presents distinct spectroscopic features to HOs from other hematophagous insects and humans. However, it is similar to that observed in D. melanogaster. Confocal analysis of immunostained tissues and western blotting using antibodies raised against recombinant enzymes have been used to track the tissue distribution of GmmHO, demonstrating that the enzyme is ubiquitously expressed in the insect, particularly in the nuclei from oenocytes, liver-like cells involved in cuticle synthesis. Such results were supported by analysis of mRNA levels, which showed higher expression levels in reproductive tissues (6.5 fold), digestive tract (2.0 fold) and fat bodies/oenocytes (1.7 fold), evincing a role in reproduction. Time series analysis of HO mRNA levels after a single blood meal revealed that GmmHO is an early blood meal induced gene in digestive tract (3.4 fold) and fat bodies/oenocytes (2.2 fold), confirming a role in the defence against heme toxicity in the digestive tract as well as unveiling possible roles in the catabolism of lipids. Thus, this work has confirmed the presence and activity of HO in a hematophagous insect and revealed both biochemical and functional aspects of the enzyme, shedding new light on the role of HO in hematophagous insects.

Background: Every year, an estimated 2.6 million stillbirths occur worldwide, with up to 98% occurring in low- and middle-income countries (LMIC). Most stillbirths are preventable. To develop strategies and take effective actions to end preventable stillbirths, a good understanding of the cause of death and its contributing factors is necessary. There is, however, a paucity of data from most LMIC settings. This study aimed to determine the cause of stillbirth in LMIC using three methods of assessment, and to assess quality of care delivered to mothers who had stillbirth. Methods: The study involved 1,563 stillbirths which occurred in 12 selected secondary and tertiary hospitals in Kenya, Malawi, Sierra Leone and Zimbabwe. The cause of death was determined by: (1) consensus of healthcare providers (HCPs) through stillbirth review; (2) expert review of cases and; (3) computer algorithms. Cause of death was classified using the classification according to Relevant Condition at Death (ReCoDe) and the International Classification of Diseases for Perinatal Mortality (ICD-PM). Quality of antenatal and intrapartum care and health system factors were reviewed using a set of criteria. Results: A total of 1,329 cases were reviewed, of which 1,267 (95.3%) stillbirths met the inclusion criteria. By country, the stillbirth rate ranged from 20.3 (Malawi) to 118.1 (Sierra Leone) per 1,000 births. The distribution of the major causes of stillbirth differed by method of assessment: asphyxia (18.5% – 37.4%), placental disorders (8.4% – 15.1%), hypertensive disorders in the mother (5.1% – 13.6%), infection (4.3% – 9.0%), cord problems (3.3% – 6.5%), and ruptured uterus due to obstructed labour (2.6% – 6.1%). Information was insufficient to assign cause of stillbirth in 17.9% - 26.0% of cases. Significant agreement was observed between cause of stillbirth assigned by the expert panel and by HCP (k=0.69; p < 0.0005) but there was a weaker agreement between expert panel and when using computer algorithms (k=0.34; p < 0.0005). Using ReCoDe, intrapartum events (mainly intrapartum asphyxia) contributed to most of the deaths, followed by maternal diseases (mainly hypertensive disorders and infection), placental and fetal conditions. With application of ICD-PM, 42.0% were antepartum, 50.7% were intrapartum and 7.3% could not be categorised. The major categories accounting for the death were: intrapartum hypoxia and fetal growth restriction. Major contributing maternal conditions in ICD-PM were: M1 (placental, cord and membranes) and M3 (other complications of labour and delivery). Poor quality of care during antenatal care was identified in 97.8% of cases, and only 30.7% of cases of Caesarean section were conducted within one hour of decision. For 414 (37.9%) stillbirths, the outcome could have been different with better care. Conclusion: Stillbirth rate was high, with high variations between countries. HCPs should be encouraged to conduct reviews and act upon findings to improve quality of care. Data requirements of computer algorithms need to be balanced between ability to find a cause and the availability of information. The new ICD-PM could work in LMIC, but there is the need for more guidance on how to handle cases of stillbirths whose time of death cannot be determined.

No description available.