Factors influencing the uptake and utilization of cervical cancer screening services among women attending public health centers in Addis Ababa, Ethiopia: mixed methods study.

BACKGROUND: Cervical cancer is the second cause of cancer deaths among Ethiopian women. Despite multifaceted government efforts, the uptake and utilization of cervical cancer screening remain very low. This study aimed to assess factors influencing the uptake and utilization of cervical cancer screening at public health centers in Addis Ababa. METHODS: A convergent parallel mixed-method study was employed to collect data through eight focus group discussions with 66 women purposively recruited from outpatient clinics, and cross-sectional face-to-face exit interviews with 80 women attending cervical cancer clinics in four high-patient volume health centers. The group interviews were tape-recorded, transcribed in Amharic, translated into English, and a thematic analysis approach was used in the analysis. Exit interview data were collected using a structured questionnaire in the Open Data Kit tool on an android tablet. STATA version 17 was used for descriptive and inferential data analyses. Statistical significance was set at p < 0.05. RESULTS: The majority of focus group discussion participants had lack of knowledge of cervical cancer and its screening services. The major barriers to the uptake of screening were inadequate public awareness, fear of the procedure, embarrassment, provider's gender, lack of male partner support, and childcare. Women aged 40 years and above were 13.9 times more likely to utilize cervical cancer screening than those under 30 years (AOR = 13.85; 95% CI: 1.40, 136.74). There was a strong preference for a female provider (AOR = 7.07; 95% CI: 1.53, 32.75) among women screened after attending antiretroviral therapy clinics and those screened due to abnormal vaginal bleeding than women referred from family planning clinics (AOR = 6.87; 95% CI: 1.02, 46.44). Safety of screening was negatively associated with women aged 30-39 (AOR = 0.045; 95% CI: 0.003, 0.696), and those who attended primary education, and secondary education and above, (AOR = 0.016; 95% CI: 0.001, 0.262), and (AOR = 0.054; 95% CI: 0.004, 0.724), respectively. CONCLUSIONS: The study identified low public awareness, inadequate provider preference, safety concerns, and poor male partner support for cervical cancer screening. We recommend the decision-makers enhance public messages, maintain provider choices, ensure safety, and engage males to improve the uptake and utilization of cervical cancer screening.

Identifying the impact of COVID-19 on health systems and lessons for future emergency preparedness: A stakeholder analysis in Kenya.

The coronavirus pandemic (COVID-19) has triggered a public health and economic crisis in high and low resource settings since the beginning of 2020. With the first case being discovered on 12th March 2020, Kenya has responded by using health and non-health strategies to mitigate the direct and indirect impact of the disease on its population. However, this has had positive and negative implications for the country's overall health system. This paper aimed to understand the pandemic's impact and develop lessons for future response by identifying the key challenges and opportunities Kenya faced during the pandemic. We conducted a qualitative study with 15 key informants, purposefully sampled for in-depth interviews from September 2020 to February 2021. We conducted direct content analysis of the transcripts to understand the stakeholder's views and perceptions of how COVID-19 has affected the Kenyan healthcare system. Most of the respondents noted that Kenya's initial response was relatively good, especially in controlling the pandemic with the resources it had at the time. This included relaying information to citizens, creating technical working groups and fostering multisectoral collaboration. However, concerns were raised regarding service disruption and impact on reproductive health, HIV, TB, and non-communicable diseases services; poor coordination between the national and county governments; shortage of personal protective equipment and testing kits; and strain of human resources for health. Effective pandemic preparedness for future response calls for improved investments across the health system building blocks, including; human resources for health, financing, infrastructure, information, leadership, service delivery and medical products and technologies. These strategies will help build resilient health systems and improve self-reliance, especially for countries transitioning from donor aid such as Kenya in the event of a pandemic.

Understanding Women's Choices: How Women's Perceptions of Quality of Care Influences Place of Delivery in a Rural Sub-County in Kenya. A Qualitative Study.

BACKGROUND: Maternal mortality is still unacceptably high in Kenya. The Kenyan Government introduced a free maternity service to overcome financial barriers to access. This policy led to a substantial increase in women's delivery options. This increase in coverage might have led to a reduction in quality of care. This study explores women's perceptions of quality of delivery services in the context of the free policy and how the perceptions lead to the choice of a place for delivery. METHODS: Our study site was Naivasha sub-County in Kenya, a rural context, whose geography encompasses pastoralists, rural agrarian, and high population density informal settlements near flower farms. Women from this area are from the lowest wealth quintile in Kenya. We conducted a qualitative study to explore the women's perceptions of quality of care based on their experiences during maternity care. The participants were women of reproductive age (18-49 years) attending antenatal care clinics at six health facilities in the sub-county. Six focus group discussions with 55 respondents were used. For inclusion, the women needed to have delivered a baby within the six months preceding the study. Interviews were recorded with consent, translated and transcribed. The interviews were analyzed using a thematic content approach. RESULTS: Four broad themes that determined the choice of health facility for delivery were identified: women's perceptions of clinical quality of care; the cost of delivery; distance to the health facility and management of primary health facilities. An unexpected theme was the presence of home deliveries amongst pastoralist women. These findings suggest that in this setting both process and structural dimensions of quality of care and financial and physical accessibility influence women's choices for place of delivery. CONCLUSION: This study expands our understanding of how women make choices regarding place of delivery. Understanding women's perceptions can provide useful insights to policy makers and facility managers on providing high quality patient centered maternity care necessary to sustain the increased utilization of maternity services at health facilities under the free maternity policy and further reductions in maternal mortality.

Sustainability drivers and inhibitors for the health system performance improvement projects in selected health facilities in Kenya: a qualitative study.

OBJECTIVES: To investigate the health managers perceived sustainability status of the health facilities institutional improvement projects and their experiences on factors that facilitated or constrained their maintenance, with intentions of informing relevant strategies or policies in Kenya's health sector. METHODS: A qualitative study, nested within a quasi-experimental study. Thirty-three project-teams of health managers were purposively selected and interviewed based on their project implementation success rates post-training. The managers had previously undergone a 9-month leadership training, complimented with facility-based team coaching around the chosen projects. The training was funded by the US Agency for International Development; however, the implementation of the projects was based on how the participants could innovatively use the existing resource to create a positive change. The projects were housed within 20 public, 9 faith-based and 4 private health facilities in 19 counties in Kenya. The interviews explored the manager's experiences in sustaining the successfully implemented projects within the (24-60 months post-training period). We asked managers to describe factors they perceived enabled or hindered the sustainability of the successfully implemented institutional improvement project. The digitally audio-recorded interviews were transcribed verbatim. Data on barriers and enablers were thematically analysed. RESULTS: Twenty-nine out of the 33 successfully implemented projects reported sustainability within periods ranging from 24 to 60 months post-training. Seven themes related to drivers of sustainability emerged, namely; programme design, stakeholder's buy-in, board members, communication, coaching, presence of change champion, devolution and political good-will. Four sustainability inhibitors identified were: human resources constraints, policy implementation, misalignment of projects with daily operations, devolution and political interference. CONCLUSIONS: The sustainability of institutional improvement strategies such as projects implemented post-leadership training in public and private health facilities depends on the quality of board members, communication management and institutionalisation of coaching culture. These findings are pertinent for planning and implementing similar health systems strengthening intervention in low-income countries.

Geographical Variability in Paromomycin Pharmacokinetics Does Not Explain Efficacy Differences between Eastern African and Indian Visceral Leishmaniasis Patients.

INTRODUCTION: Intramuscular paromomycin monotherapy to treat visceral leishmaniasis (VL) has been shown to be effective for Indian patients, while a similar regimen resulted in lower efficacy in Eastern Africa, which could be related to differences in paromomycin pharmacokinetics. METHODS: Pharmacokinetic data were available from two randomized controlled trials in VL patients from Eastern Africa and India. African patients received intramuscular paromomycin monotherapy (20 mg/kg for 21 days) or combination therapy (15 mg/kg for 17 days) with sodium stibogluconate. Indian patients received paromomycin monotherapy (15 mg/kg for 21 days). A population pharmacokinetic model was developed for paromomycin in Eastern African and Indian VL patients. RESULTS: Seventy-four African patients (388 observations) and 528 Indian patients (1321 observations) were included in this pharmacokinetic analysis. A one-compartment model with first-order kinetics of absorption and elimination best described paromomycin in plasma. Bioavailability (relative standard error) was 1.17 (5.18%) times higher in Kenyan and Sudanese patients, and 2.46 (24.5%) times higher in Ethiopian patients, compared with Indian patients. Ethiopian patients had an approximately fourfold slower absorption rate constant of 0.446 h-1 (18.2%). Area under the plasma concentration-time curve for 24 h at steady-state (AUCτ,SS) for 15 mg/kg/day (median [interquartile range]) was higher in Kenya and Sudan (172.7 µg·h/mL [145.9-214.3]) and Ethiopia (230.1 µg·h/mL [146.3-591.2]) compared with India (97.26 µg·h/mL [80.83-123.4]). CONCLUSION: The developed model provides detailed insight into the pharmacokinetic differences among Eastern African countries and India, however the resulting differences in paromomycin exposure do not seem to explain the geographical differences in paromomycin efficacy in the treatment of VL patients.

Understanding what women want: eliciting preference for delivery health facility in a rural subcounty in Kenya, a discrete choice experiment.

OBJECTIVE: To identify what women want in a delivery health facility and how they rank the attributes that influence the choice of a place of delivery. DESIGN: A discrete choice experiment (DCE) was conducted to elicit rural women's preferences for choice of delivery health facility. Data were analysed using a conditional logit model to evaluate the relative importance of the selected attributes. A mixed multinomial model evaluated how interactions with sociodemographic variables influence the choice of the selected attributes. SETTING: Six health facilities in a rural subcounty. PARTICIPANTS: Women aged 18-49 years who had delivered within 6 weeks. PRIMARY OUTCOME: The DCE required women to select from hypothetical health facility A or B or opt-out alternative. RESULTS: A total of 474 participants were sampled, 466 participants completed the survey (response rate 98%). The attribute with the strongest association with health facility preference was having a kind and supportive healthcare worker (ß=1.184, p<0.001), second availability of medical equipment and drug supplies (ß=1.073, p<0.001) and third quality of clinical services (ß=0.826, p<0.001). Distance, availability of referral services and costs were ranked fourth, fifth and sixth, respectively (ß=0.457, p<0.001; ß=0.266, p<0.001; and ß=0.000018, p<0.001). The opt-out alternative ranked last suggesting a disutility for home delivery (ß=-0.849, p<0.001). CONCLUSION: The most highly valued attribute was a process indicator of quality of care followed by technical indicators. Policymakers need to consider women's preferences to inform strategies that are person centred and lead to improvements in quality of care during delivery.

'We just look at the well-being of the baby and not the money required': a qualitative study exploring experiences of quality of maternity care among women in Nairobi's informal settlements in Kenya.

OBJECTIVE: To examine how women living in an informal settlement in Nairobi perceive the quality of maternity care and how it influences their choice of a delivery health facility. DESIGN: Qualitative study. SETTINGS: Dandora, an informal settlement, Nairobi City in Kenya. PARTICIPANTS: Six focus group discussions with 40 purposively selected women aged 18-49 years at six health facilities. RESULTS: Four broad themes were identified: (1) perceived quality of the delivery services, (2) financial access to delivery service, (3) physical amenities at the health facility, and (4) the 2017 health workers' strike.The four facilitators that influenced women to choose a private health facility were: (1) interpersonal treatment at health facilities, (2) perceived quality of clinical services, (3) financial access to health services at the facility, and (4) the physical amenities at the health facility. The three barriers to choosing a private facility were: (1) poor quality clinical services at low-cost health facilities, (2) shortage of specialist doctors, and (3) referral to public health facilities during emergencies.The facilitators that influenced women to choose a public facility were: (1) physical amenities for dealing with obstetric emergencies and (2) early referral to public maternity during antenatal care services. Barriers to choosing a public facility were: (1) perception of poor quality clinical services, (2) concerns over security for newborns at tertiary health facilities, (3) fear of mistreatment during delivery, (4) use of unsupervised trainee doctors for deliveries, (5) poor quality of physical amenities, and (6) inadequate staffing. CONCLUSION: The study provides insights into decision-making processes for women when choosing a delivery facility by identifying critical attributes that they value and how perceptions of quality influence their choices.

How do fatalistic beliefs affect the attitudes and pedestrian behaviours of road users in different countries? A cross-cultural study.

This paper reports on an exploratory investigation of the influence of five different fatalistic belief constructs (divine control, luck, helplessness, internality, and general fatalism) on three classes of self-reported pedestrian behaviours (memory and attention errors, rule violations, and aggressive behaviours) and on respondents' general attitudes to road safety, and how relationships between constructs differ across countries. A survey of over 3400 respondents across Bangladesh, China, Kenya, Thailand, the UK, and Vietnam revealed a similar pattern for most of the relationships assessed, in most countries; those who reported higher fatalistic beliefs or more external attributions of causality also reported performing riskier pedestrian behaviours and holding more dangerous attitudes to road safety. The strengths of relationships between constructs did, however, differ by country, behaviour type, and aspect of fatalism. One particularly notable country difference was that in Bangladesh and, to a lesser extent, in Kenya, a stronger belief in divine influence over one's life was associated with safer attitudes and behaviours, whereas where significant relationships existed in the other countries the opposite was true. In some cases, the effect of fatalistic beliefs on self-reported behaviours was mediated through attitudes, in other cases the effect was direct. Results are discussed in terms of the need to consider the effect of locus of control and attributions of causality on attitudes and behaviours, and the need to understand the differences between countries therein.

An Assessment of Impact of Leadership Training on Health System Performance in Selected Counties in Kenya.

Introduction: The provision of health care services in Kenya was devolved from the national government to the counties in 2013. Evidence suggests that health system performance in Kenya remains poor. The main issue is poor leadership resulting in poor health system performance. However, most training in Kenya focuses on "leaders" (individual) development as opposed to "leadership" training (development of groups from an organization). The purpose of that study was to explore the impact of leadership training on health system performance in selected counties in Kenya. Methods: A quasi-experimental time-series design was employed. Pretest, posttest control-group design was utilized to find out whether the leadership development program positively contributed to the improvement of health system performance indicators compared with the non-trained managers. Questionnaires were administered to 31 trained health managers from the public, private for-profit, and private not-for-profit health institutions within the same counties. Results: The pretest and posttest means for all the six health system (HS) pillar indicators of the treatment group were higher than those of the control group. The regression method to estimate the DID structural model used to calculate the "fact" and "counterfactual" revealed that training had a positive impact on the intended outcome on the service delivery, information, leadership and governance, human resources, finance, and medical products with impact value ≥1 (57.2). Conclusion: The study findings support both hypotheses that trained health care management teams had a significant difference in the implementation status of priority projects and, hence, had a significant impact on health system performance indicators compared with non-trained managers.

From strategy to action: a qualitative study on salient factors influencing knowledge transfer in project-based experiential learning in healthcare organisations in Kenya.

OBJECTIVES: Knowledge transfer is recognised as a key determinant of organisational competitiveness. Existing literature on the transfer of knowledge and skills imply diminutive return on investment in training and development due to the low application of learnt knowledge. Following devolution of health services provision to new counties in Kenya in 2013, Strathmore Business School designed an experiential facility improvement project-based leadership training programme for healthcare managers in the new counties. Selected healthcare management teams participated in the leadership training to improve health systems performance in the devolved counties in Kenya. Despite similar training, the projects implementation contexts were different, leading to different implementation completion rates. The aim of this study was to investigate the reasons for this disparity and then recommend solutions. DESIGN: A qualitative study using semi-structured interviews. A thematic framework approach was used in data analysis. SETTING AND PARTICIPANTS: Thirty-nine projects teams constituting; 33 successful and 6 unsuccessful project teams, were purposively selected based on their project implementation success rates at the end of the leadership training. The managers had undertaken a team-based institutional improvement project. The prioritised projects were housed within; 23 public, 10 faith-based and 6 private health facilities in 19 counties in Kenya. RESULTS: Our findings indicate projects completion rates were influenced by (training design, work environment climate, trainee characteristics, team-based coaching and leveraging on occurring opportunities). Transfer barriers were (inadequate management support, inadequate team and staff support, high staff turnover, misalignment of board's verses manager's priorities, missing technical expertise, endemic strikes, negative politics and poor communication). Recommendations were (need-driven curriculum, effective allocation and efficient utilisation of resources, proper prioritisation, effective communication, longitudinal coaching and work-teams recruitment). CONCLUSION: The findings reveal that unless training interventions are informed by a need-driven curriculum customised to real-world work teams, the potential knowledge and skill transfer can be thwarted.

Vulnerable road users in low-, middle-, and high-income countries: Validation of a Pedestrian Behaviour Questionnaire.

The primary aim of this study was to validate the short version of a Pedestrian Behaviour Questionnaire across six culturally and economically distinct countries; Bangladesh, China, Kenya, Thailand, the UK, and Vietnam. The questionnaire comprised 20 items that asked respondents to rate the extent to which they perform certain types of pedestrian behaviours, with each behaviour belonging to one of five categories identified in previous literature; violations, errors, lapses, aggressive behaviours, and positive behaviours. The sample consisted of 3423 respondents across the six countries. Confirmatory factor analysis was used to assess the fit of the data to the five-factor structure, and a four-factor structure in which violations and errors were combined into one factor (seen elsewhere in the literature). For some items, factor loadings were unacceptably low, internal reliability was low for two of the sub-scales, and model fit indices were generally unacceptable for both models. As such, only the violations, lapses, and aggressions sub-scales were retained (those with acceptable reliability and factor loadings), and the three-factor model tested. Although results suggest that the violations sub-scale may need additional attention, the three-factor solution showed the best fit to the data. The resulting 12-item scale is discussed with regards to country differences, and with respect to its utility as a research tool in cross-cultural studies of road user behaviour.

Better Board Education for Better Leadership and Management in the Health Sectors of Low and Middle Income Countries.

Board member education must be elevated within the curricula of leadership development programming in Low and Middle Income Countries (LMICs) across the globe. When properly trained and supported, the community, business, and health sector leaders serving on these boards can create the conditions within which those who deliver and manage health services are more likely to successfully achieve the mission of their organizations. The importance of incorporating education for governing body members into health sector leadership development programming, and three strategies for board development, are defined in in this article.

Partial HIV C2V3 envelope sequence analysis reveals association of coreceptor tropism, envelope glycosylation and viral genotypic variability among Kenyan patients on HAART.

BACKGROUND: HIV-1 is highly variable genetically and at protein level, a property it uses to subvert antiviral immunity and treatment. The aim of this study was to assess if HIV subtype differences were associated with variations in glycosylation patterns and co-receptor tropism among HAART patients experiencing different virologic treatment outcomes. METHODS: A total of 118 HIV env C2V3 sequence isolates generated previously from 59 Kenyan patients receiving highly active antiretroviral therapy (HAART) were examined for tropism and glycosylation patterns. For analysis of Potential N-linked glycosylation sites (PNGs), amino acid sequences generated by the NCBI's Translate tool were applied to the HIVAlign and the N-glycosite tool within the Los Alamos Database. Viral tropism was assessed using Geno2Pheno (G2P), WebPSSM and Phenoseq platforms as well as using Raymond's and Esbjörnsson's rules. Chi square test was used to determine independent variables association and ANOVA applied on scale variables. RESULTS: At respective False Positive Rate (FPR) cut-offs of 5% (p = 0.045), 10% (p = 0.016) and 20% (p = 0.005) for CXCR4 usage within the Geno2Pheno platform, HIV-1 subtype and viral tropism were significantly associated in a chi square test. Raymond's rule (p = 0.024) and WebPSSM (p = 0.05), but not Phenoseq or Esbjörnsson showed significant associations between subtype and tropism. Relative to other platforms used, Raymond's and Esbjörnsson's rules showed higher proportions of X4 variants, while WebPSSM resulted in lower proportions of X4 variants across subtypes. The mean glycosylation density differed significantly between subtypes at positions, N277 (p = 0.034), N296 (p = 0.036), N302 (p = 0.034) and N366 (p = 0.004), with HIV-1D most heavily glycosylated of the subtypes. R5 isolates had fewer PNGs than X4 isolates, but these differences were not significant except at position N262 (p = 0.040). Cell-associated isolates from virologic treatment success subjects were more glycosylated than cell-free isolates from virologic treatment failures both for the NXT (p = 0.016), and for all the patterns (p = 0.011). CONCLUSION: These data reveal significant associations of HIV-1 subtype diversity, viral co-receptor tropism, viral suppression and envelope glycosylation. These associations have important implications for designing therapy and vaccines against HIV. Heavy glycosylation and preference for CXCR4 usage of HIV-1D may explain rapid disease progression in patients infected with these strains.

Plasma nevirapine concentrations predict virological and adherence failure in Kenyan HIV-1 infected patients with extensive antiretroviral treatment exposure.

Treatment failure is a key challenge in the management of HIV-1 infection. We conducted a mixed-model survey of plasma nevirapine (NVP) concentrations (cNVP) and viral load in order to examine associations with treatment and adherence outcomes among Kenyan patients on prolonged antiretroviral therapy (ART). Blood plasma was collected at 1, 4 and 24 hours post-ART dosing from 58 subjects receiving NVP-containing ART and used to determine cNVP and viral load (VL). Median duration of treatment was 42 (range, 12-156) months, and 25 (43.1%) of the patients had virologic failure (VF). cNVP was significantly lower for VF than non- VF at 1hr (mean, 2,111ng/ml vs. 3,432ng/ml, p = 0.003) and at 4hr (mean 1,625ng/ml vs. 3,999ng/ml, p = 0.001) but not at 24hr post-ART dosing. Up to 53.4%, 24.1% and 22.4% of the subjects had good, fair and poor adherence respectively. cNVP levels peaked and were > = 3µg.ml at 4 hours in a majority of patients with good adherence and those without VF. Using a threshold of 3µg/ml for optimal therapeutic nevirapine level, 74% (43/58), 65.5% (38/58) and 86% (50/58) of all patients had sub-therapeutic cNVP at 1, 4 and 24 hours respectively. cNVP at 4 hours was associated with adherence (p = 0.05) and virologic VF (p = 0.002) in a chi-square test. These mean cNVP levels differed significantly in non-parametric tests between adherence categories at 1hr (p = 0.005) and 4hrs (p = 0.01) and between ART regimen categories at 1hr (p = 0.004) and 4hrs (p<0.0001). Moreover, cNVP levels correlated inversely with VL (p< = 0.006) and positively with adherence behavior. In multivariate tests, increased early peak NVP (cNVP4) was independently predictive of lower VL (p = 0.002), while delayed high NVP peak (cNVP24) was consistent with increased VL (p = 0.033). These data strongly assert the need to integrate plasma concentrations of NVP and that of other ART drugs into routine ART management of HIV-1 patients.

Co-Infection Burden of Hepatitis C Virus and Human Immunodeficiency Virus among Injecting Heroin Users at the Kenyan Coast.

BACKGROUND: Injection drug use is steadily rising in Kenya. We assessed the prevalence of both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infections among injecting heroin users (IHUs) at the Kenyan Coast. METHODS: A total of 186 IHUs (mean age, 33 years) from the Omari rehabilitation center program in Malindi were consented and screened for HIV-1 and HCV by serology and PCR and their CD4 T-cells enumerated by FACS. RESULTS: Prevalence of HIV-1 was 87.5%, that of HCV was 16.4%, co-infection was 17.9% and 18/152 (11.8%) were uninfected. Only 5.26% of the HIV-1 negative injectors were HCV positive. Co-infection was higher among injectors aged 30 to 40 years (20.7%) and among males (22.1%) than comparable groups. About 35% of the injectors were receiving antiretroviral treatment (ART). Co-infection was highest among injectors receiving D4T (75%) compared to those receiving AZT (21.6%) or TDF (10.5%) or those not on ART (10.5%). Mean CD4 T-cells were 404 (95% CI, 365 - 443) cells/mm3 overall, significantly lower for co-infected (mean, 146; 95% CI 114 - 179 cells/mm3) than HIV mono infected (mean, 437, 95% CI 386 - 487 cells/mm3, p<0.001) or uninfected (mean, 618, 95% CI 549 - 687 cells/mm3, p<0.001) injectors and lower for HIV mono-infected than uninfected injectors (p=0.002). By treatment arm, CD4 T-cells were lower for injectors receiving D4T (mean, 78; 95% CI, 0.4 - 156 cells/mm3) than TDF (mean 607, 95% CI, 196 - 1018 cells/mm3, p=0.005) or AZT (mean 474, 95% CI -377 - 571 cells/mm3, p=0.004). CONCLUSION: Mono and dual infections with HIV-1 and HCV is high among IHUs in Malindi, but ART coverage is low. The co-infected IHUs have elevated risk of immunodeficiency due to significantly depressed CD4 T-cell numbers. Coinfection screening, treatment-as-prevention for both HIV and HCV and harm reduction should be scaled up to alleviate infection burden.

Plasma and cerebrospinal proteomes from children with cerebral malaria differ from those of children with other encephalopathies.

Clinical signs and symptoms of cerebral malaria in children are nonspecific and are seen in other common encephalopathies in malaria-endemic areas. This makes accurate diagnosis difficult in resource-poor settings. Novel malaria-specific diagnostic and prognostic methods are needed. We have used 2 proteomic strategies to identify differentially expressed proteins in plasma and cerebrospinal fluid from children with a diagnosis of cerebral malaria, compared with those with a diagnosis of malaria-slide-negative acute bacterial meningitis and other nonspecific encephalopathies. Here we report the presence of differentially expressed proteins in cerebral malaria in both plasma and cerebrospinal fluid that could be used to better understand pathogenesis and help develop more-specific diagnostic methods. In particular, we report the expression of 2 spectrin proteins that have known Plasmodium falciparum-binding partners involved in the stability of the infected red blood cell, suppressing further invasion and possibly enhancing the red blood cell's ability to sequester in microvasculature.

Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation.

BACKGROUND: Severe malnutrition is frequently complicated by sepsis, leading to high case fatality. Oral ciprofloxacin is a potential alternative to the standard parenteral ampicillin/gentamicin combination, but its pharmacokinetics in malnourished children is unknown. METHODS: Ciprofloxacin (10 mg/kg, 12 hourly) was administered either 2 h before or up to 2 h after feeds to Kenyan children hospitalized with severe malnutrition. Four plasma ciprofloxacin concentrations were measured over 24 h. Population analysis with NONMEM investigated factors affecting the oral clearance (CL) and the oral volume of distribution (V). Monte Carlo simulations investigated dosage regimens to achieve a target AUC(0-24)/MIC ratio of ≥125. RESULTS: Data comprised 202 ciprofloxacin concentration measurements from 52 children aged 8-102 months. Absorption was generally rapid but variable; C(max) ranged from 0.6 to 4.5 mg/L. Data were fitted by a one-compartment model with first-order absorption and lag. The parameters were CL (L/h) = 42.7 (L/h/70 kg) × [weight (kg)/70](0.75) × [1 + 0.0368 (Na(+) - 136)] × [1 - 0.283 (high risk)] and V (L) = 372 × (L/70 kg) × [1 + 0.0291 (Na(+) - 136)]. Estimates of AUC(0-24) ranged from 8 to 61 mg·h/L. The breakpoint for Gram-negative organisms was <0.06 mg/L with doses of 20 mg/kg/day and <0.125 mg/L with doses of 30 or 45 mg/kg/day. The cumulative fraction of response with 30 mg/kg/day was ≥80% for Escherichia coli, Klebsiella pneumoniae and Salmonella species, but <60% for Pseudomonas aeruginosa. CONCLUSIONS: An oral ciprofloxacin dose of 10 mg/kg three times daily (30 mg/kg/day) may be a suitable alternative antibiotic for the management of sepsis in severely malnourished children. Absorption was unaffected by the simultaneous administration of feeds.

Global proteomic analysis of plasma from mice infected with Plasmodium berghei ANKA using two dimensional gel electrophoresis and matrix assisted laser desorption ionization-time of flight mass spectrometry.

BACKGROUND: A global proteomic strategy was used to identify proteins, which are differentially expressed in the murine model of severe malaria in the hope of facilitating future development of novel diagnostic, disease monitoring and treatment strategies. METHODS: Mice (4-week-old CD1 male mice) were infected with Plasmodium berghei ANKA strain, and infection allowed to establish until a parasitaemia of 30% was attained. Total plasma and albumin depleted plasma samples from infected and control (non-infected) mice were separated by two-dimensional gel electrophoresis (2-DE). After staining, the gels were imaged and differential protein expression patterns were interrogated using image analysis software. Spots of interest were then digested using trypsin and the proteins identified using matrix-assisted laser desorption and ionization-time of flight (MALDI-TOF) mass spectrometry (MS) and peptide mass fingerprinting software. RESULTS: Master gels of control and infected mice, and the corresponding albumin depleted fractions exhibited distinctly different 2D patterns comparing control and infected plasma, respectively. A wide range of proteins demonstrated altered expression including; acute inflammatory proteins, transporters, binding proteins, protease inhibitors, enzymes, cytokines, hormones, and channel/receptor-derived proteins. CONCLUSIONS: Malaria-infection in mice results in a wide perturbation of the host serum proteome involving a range of proteins and functions. Of particular interest is the increased secretion of anti-inflammatory and anti apoptotic proteins.

A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers.

BACKGROUND: Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. METHODS: Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. RESULTS: The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C(max)) was 160-200 nM and after 6 hours, the effective concentration (C(eff)) was <150 nM. CONCLUSION: Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C(eff) of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

Determination of ciprofloxacin in human plasma using high-performance liquid chromatography coupled with fluorescence detection: application to a population pharmacokinetics study in children with severe malnutrition.

Clinical pharmacokinetic studies of ciprofloxacin require accurate and precise measurement of plasma drug concentrations. We describe a rapid, selective and sensitive HPLC method coupled with fluorescence detection for determination of ciprofloxacin in human plasma. Internal standard (IS; sarafloxacin) was added to plasma aliquots (200 µL) prior to protein precipitation with acetonitrile. Ciprofloxacin and IS were eluted on a Synergi Max-RP analytical column (150 mm×4.6 mm i.d., 5 µm particle size) maintained at 40°C. The mobile phase comprised a mixture of aqueous orthophosphoric acid (0.025 M)/methanol/acetonitrile (75/13/12%, v/v/v); the pH was adjusted to 3.0 with triethylamine. A fluorescence detector (excitation/emission wavelength of 278/450 nm) was used. Retention times for ciprofloxacin and IS were approximately 3.6 and 7.0 min, respectively. Calibration curves of ciprofloxacin were linear over the concentration range of 0.02-4 µg/mL, with correlation coefficients (r(2))≥0.998. Intra- and inter-assay relative standard deviations (SD) were <8.0% and accuracy values ranged from 93% to 105% for quality control samples (0.2, 1.8 and 3.6 µg/mL). The mean (SD) extraction recoveries for ciprofloxacin from spiked plasma at 0.08, 1.8 and 3.6 µg/mL were 72.8±12.5% (n=5), 83.5±5.2% and 77.7±2.0%, respectively (n=8 in both cases). The recovery for IS was 94.5±7.9% (n=15). The limits of detection and quantification were 10 ng/mL and 20 ng/mL, respectively. Ciprofloxacin was stable in plasma for at least one month when stored at -15°C to -25°C and -70°C to -90°C. This method was successfully applied to measure plasma ciprofloxacin concentrations in a population pharmacokinetics study of ciprofloxacin in malnourished children.