Diagnostic imaging capabilities of the Ocelot -Optical Coherence Tomography System, ex-vivo evaluation and clinical relevance.

BACKGROUND: Optical coherence tomography (OCT) is a high-resolution sub-surface imaging modality using near-infrared light to provide accurate and high contrast intra-vascular images. This enables accurate assessment of diseased arteries before and after intravascular intervention. This study was designed to corroborate diagnostic imaging equivalence between the Ocelot and the Dragonfly OCT systems with regards to the intravascular features that are most important in clinical management of patients with atherosclerotic vascular disease. These intravascular features were then corroborated in vivo during treatment of peripheral arterial disease (PAD) pathology using the Ocelot catheter. METHODS: In order to compare the diagnostic information obtained by Ocelot (Avinger Inc., Redwood City, CA) and Dragonfly (St. Jude Medical, Minneapolis, MN) OCT systems, we utilized ex-vivo preparations of arterial segments. Ocelot and Dragonfly catheters were inserted into identical cadaveric femoral peripheral arteries for image acquisition and interpretation. Three independent physician interpreters assessed the images to establish accuracy and sensitivity of the diagnostic information. Histologic evaluation of the corresponding arterial segments provided the gold standard for image interpretation. In vivo clinical images were obtained during therapeutic interventions that included crossing of peripheral chronic total occlusions (CTOs) using the Ocelot catheter. RESULTS: Strong concordance was demonstrated when matching image characteristics between both OCT systems and histology. The Dragonfly and Ocelot system's vessel features were interpreted with high sensitivity (91.1-100%) and specificity (86.7-100%). Inter-observer concordance was documented with excellent correlation across all vessel features. The clinical benefit that the Ocelot OCT system provided was demonstrated by comparable procedural images acquired at the point of therapy. CONCLUSIONS: The study demonstrates equivalence of image acquisition and consistent physician interpretation of images acquired by the Ocelot and the Dragonfly OCT systems in-spite of distinct image processing algorithms and catheter configurations. This represents a dramatic shift away from both fluoroscopic imaging and diagnostic-only OCT imaging during peripheral arterial intervention towards therapeutic devices that incorporate real time diagnostic OCT imaging. In the clinical practice, these diagnostic capabilities have translated to best-in-class safety and efficacy for CTO crossing using the Ocelot catheter.

A randomized controlled trial of standard versus intensified tuberculosis diagnostics on treatment decisions by physicians in Northern Tanzania.

BACKGROUND: Routine tuberculosis culture remains unavailable in many high-burden areas, including Tanzania. This study sought to determine the impact of providing mycobacterial culture results over standard of care [unconcentrated acid-fast (AFB) smears] on management of persons with suspected tuberculosis. METHODS: Adults and children with suspected tuberculosis were randomized to standard (direct AFB smear only) or intensified (concentrated AFB smear and tuberculosis culture) diagnostics and followed for 8 weeks. The primary endpoint was appropriate treatment (i.e. antituberculosis therapy for those with tuberculosis, no antituberculous therapy for those without tuberculosis). RESULTS: Seventy participants were randomized to standard (n = 37, 53%) or intensive (n = 33, 47%) diagnostics. At 8 weeks, 100% (n = 22) of participants in follow up randomized to intensive diagnostics were receiving appropriate care, vs. 22 (88%) of 25 participants randomized to standard diagnostics (p = 0.14). Overall, 18 (26%) participants died; antituberculosis therapy was associated with lower mortality (9% who received antiuberculosis treatment died vs. 26% who did not, p = 0.04). CONCLUSIONS: Under field conditions in a high burden setting, the impact of intensified diagnostics was blunted by high early mortality. Enhanced availability of rapid diagnostics must be linked to earlier access to care for outcomes to improve.

Invasive bacterial and fungal infections among hospitalized HIV-infected and HIV-uninfected adults and adolescents in northern Tanzania.

BACKGROUND: few studies describe patterns of human immunodeficiency virus (HIV) co-infections in African hospitals in the antiretroviral therapy (ART) era. METHODS: we enrolled consecutive admitted patients aged ≥ 13 years with oral temperature of ≥ 38.0°C during 1 year in Moshi, Tanzania. A standardized clinical history and physical examination was done and hospital outcome recorded. HIV antibody testing, aerobic and mycobacterial blood cultures, and malaria film were performed. HIV-infected patients also received serum cryptococcal antigen testing and CD4(+) T lymphocyte count (CD4 cell count). RESULTS: of 403 patients enrolled, the median age was 38 years (range, 14-96 years), 217 (53.8%) were female, and 157 (39.0%) were HIV-infected. Of HIV-infected patients, the median CD4 cell count was 98 cells/µL (range, 1-1,105 cells/ µL), 20 (12.7%) were receiving ART, and 29 (18.5%) were receiving trimethoprim-sulfamethoxazole prophylaxis. There were 112 (27.7%) patients who had evidence of invasive disease, including 26 (23.2%) with Salmonella serotype Typhi infection, 24 (21.4%) with Streptococcus pneumoniae infection, 17 (15.2%) with Cryptococcus neoformans infection, 12 (10.7%) with Mycobacterium tuberculosis complex infection, 8 (7.1%) with Plasmodium falciparum infection, and 7 (6.3%) with Escherichia coli infection. HIV infection was associated with M. tuberculosis and C. neoformans bloodstream infection but not with E. coli, S. pneumoniae, or P. falciparum infection. HIV infection appeared to be protective against Salmonella. Typhi bloodstream infection (odds ratio, .12; P = .001). CONCLUSIONS: while Salmonella Typhi and S. pneumoniae were the most common causes of invasive infection overall, M. tuberculosis and C. neoformans were the leading causes of bloodstream infection among HIV-infected inpatients in Tanzania in the ART era. We demonstrate a protective effect of HIV against Salmonella. Typhi bloodstream infection in this setting. HIV co-infections continue to account for a large proportion of febrile admissions in Tanzania.

Invasive bacterial and fungal infections among hospitalized HIV-infected and HIV-uninfected children and infants in northern Tanzania.

OBJECTIVE: To describe the contribution of paediatric HIV and of HIV co-infections to admissions to a hospital in Moshi, Tanzania, using contemporary laboratory methods. METHODS: During 1 year, we enrolled consecutively admitted patients aged ≥2 months and <13 years with current or recent fever. All patients underwent standardized clinical history taking, a physical examination and HIV antibody testing; standard aerobic blood cultures and malaria film were also done, and hospital outcome was recorded. Early infant HIV diagnosis by HIV-1 RNA PCR was performed on those aged <18 months. HIV-infected patients also received serum cryptococcal antigen testing and had their CD4-positive T-lymphocyte count and percent determined. RESULTS: A total of 467 patients were enrolled whose median age was 2 years (range 2 months-13 years); Of those patients, 57.2% were female and 12.2% were HIV-infected. Admission clinical diagnosis of HIV disease was made in 10.7% and of malaria in 60.4%. Of blood cultures, 5.8% grew pathogens; of these 25.9% were Salmonella enterica (including 6 Salmonella Typhi) and 22.2%Streptococcus pneumoniae. Plasmodium falciparum was identified on blood film of 1.3%. HIV infection was associated with S. pneumoniae (odds ratio 25.7, 95% CI 2.8, 234.0) bloodstream infection (BSI), but there was no evidence of an association with Escherichia coli or P. falciparum; Salmonella Typhi BSI occurred only among HIV-uninfected participants. The sensitivity and specificity of an admission clinical diagnosis of malaria were 100% and 40.3%; and for an admission diagnosis of bloodstream infection, they were 9.1% and 86.4%, respectively. CONCLUSION: Streptococcus pneumoniae is a leading cause of bloodstream infection among paediatric admissions in Tanzania and is closely associated with HIV infection. Malaria was over-diagnosed clinically, whereas invasive bacterial disease was underestimated. HIV and HIV co-infections contribute to a substantial proportion of paediatric febrile admissions, underscoring the value of routine HIV testing.

Birthweight, preterm birth and perinatal mortality: a comparison of black babies in Tanzania and the USA.

OBJECTIVES: Adverse conditions in Africa produce some of the highest rates of infant mortality in the world. Fetal growth restriction and preterm delivery are commonly regarded as major pathways through which conditions in the developing world affect infant survival. The aim of this article was to compare patterns of birthweight, preterm delivery, and perinatal mortality between black people in Tanzania and the USA. DESIGN: Registry-based study. SETTINGS: Referral hospital data from North Eastern Tanzania and US Vital Statistics. SAMPLE: 14 444 singleton babies from a hospital-based registry (1999-2006) and 3 530 335 black singletons from US vital statistics (1995-2000). MAIN OUTCOME MEASURES: Birthweight, gestational age and perinatal mortality. METHODS: Restricting our study to babies born at least 500g, we compared birthweight, gestational age, and perinatal mortality (stillbirths and deaths in the first week) in the two study populations. RESULTS: Perinatal mortality in the Tanzanian sample was 41/1 000, compared with 10/1 000 among USA blacks. Tanzanian babies were slightly smaller on average (43g), but fewer were preterm (<37 weeks) (10.0 vs. 16.2%). Applying the USA weight-specific mortality rates to Tanzanian babies born at term suggested that birthweight does not play a role in their increased mortality relative to USA blacks. CONCLUSIONS: Higher mortality independent of birthweight and preterm delivery for Tanzanian babies suggests the need to address the contribution of other pathways to further reduce the excess perinatal mortality.

Alterations in early cytokine-mediated immune responses to Plasmodium falciparum infection in Tanzanian children with mineral element deficiencies: a cross-sectional survey.

BACKGROUND: Deficiencies in vitamins and mineral elements are important causes of morbidity in developing countries, possibly because they lead to defective immune responses to infection. The aim of the study was to assess the effects of mineral element deficiencies on early innate cytokine responses to Plasmodium falciparum malaria. METHODS: Peripheral blood mononuclear cells from 304 Tanzanian children aged 6-72 months were stimulated with P. falciparum-parasitized erythrocytes obtained from in vitro cultures. RESULTS: The results showed a significant increase by 74% in geometric mean of TNF production in malaria-infected individuals with zinc deficiency (11% to 240%; 95% CI). Iron deficiency anaemia was associated with increased TNF production in infected individuals and overall with increased IL-10 production, while magnesium deficiency induced increased production of IL-10 by 46% (13% to 144%) in uninfected donors. All donors showed a response towards IL-1beta production, drawing special attention for its possible protective role in early innate immune responses to malaria. CONCLUSIONS: In view of these results, the findings show plasticity in cytokine profiles of mononuclear cells reacting to malaria infection under conditions of different micronutrient deficiencies. These findings lay the foundations for future inclusion of a combination of precisely selected set of micronutrients rather than single nutrients as part of malaria vaccine intervention programmes in endemic countries.

Effect of nutrient deficiencies on in vitro Th1 and Th2 cytokine response of peripheral blood mononuclear cells to Plasmodium falciparum infection.

BACKGROUND: An appropriate balance between pro-inflammatory and anti-inflammatory cytokines that mediate innate and adaptive immune responses is required for effective protection against human malaria and to avoid immunopathology. In malaria endemic countries, this immunological balance may be influenced by micronutrient deficiencies. METHODS: Peripheral blood mononuclear cells from Tanzanian preschool children were stimulated in vitro with Plasmodium falciparum-parasitized red blood cells to determine T-cell responses to malaria under different conditions of nutrient deficiencies and malaria status. RESULTS: The data obtained indicate that zinc deficiency is associated with an increase in TNF response by 37%; 95% CI: 14% to 118% and IFN-gamma response by 74%; 95% CI: 24% to 297%. Magnesium deficiency, on the other hand, was associated with an increase in production of IL-13 by 80%; 95% CI: 31% to 371% and a reduction in IFN-gamma production. These results reflect a shift in cytokine profile to a more type I cytokine profile and cell-cell mediated responses in zinc deficiency and a type II response in magnesium deficiency. The data also reveal a non-specific decrease in cytokine production in children due to iron deficiency anaemia that is largely associated with malaria infection status. CONCLUSIONS: The pathological sequels of malaria potentially depend more on the balance between type I and type II cytokine responses than on absolute suppression of these cytokines and this balance may be influenced by a combination of micronutrient deficiencies and malaria status.

Prevalence of in-hospital complications in 500 patients undergoing percutaneous coronary intervention treated with heparin 5000 IU administered systemically versus 500 age-matched and sex-matched patients treated with heparin 70 IU/kg administered systemically.

We investigated the prevalence of in-hospital complications in 500 patients undergoing percutaneous coronary intervention (PCI) treated with heparin 5000 IU administered systemically (group 1) at the time of PCI versus in 500 age-matched and sex-matched patients undergoing PCI treated with heparin 70 IU/kg administered systemically (group 2) at the time of PCI. There was no significant difference in baseline characteristics, indications for PCI, cardiovascular drug therapy at the time of PCI, prevalence of 1-vessel, 2-vessel, and 3-vessel obstructive coronary artery disease, and in-hospital complications between the 2 groups. In-hospital death occurred in 0.2% of group 1 patients versus 0.8% of group 2 patients. Non-ST-segment elevation myocardial infarction occurred in 0.2% of group 1 patients versus 0.4% of group 2 patients. Stroke occurred in 0.2% of group 1 patients versus 0.2% of group 2 patients. Stent thrombosis occurred in 0.2% of group 1 patients versus 0.8% of group 2 patients. Occlusion of a side branch occurred in 0.2% of group 1 patients versus 0.4% of group 2 patients. A hematoma needing intervention occurred in 0.2% of group 1 patients versus 0.2% of group 2 patients. Regression analysis showed that none of the differences between the 2 groups were significant. The sample size was adequate to conclude that a fixed low dose of heparin 5000 IU administered systemically at the time of PCI is noninferior to standard therapy with heparin.

Total lymphocyte count and World Health Organization pediatric clinical stage as markers to assess need to initiate antiretroviral therapy among human immunodeficiency virus-infected children in Moshi, Northern Tanzania.

BACKGROUND: The World Health Organization (WHO) has recommended the use of clinical staging alone and with total lymphocyte count to identify HIV infected children in need of antiretroviral therapy (ART) in resource-limited settings, when CD4 cell count is not available. METHODS: We prospectively enrolled children obtaining care for HIV infection at the Kilimanjaro Christian Medical Centre Pediatric Infectious Diseases Clinic in Moshi, Tanzania between March 2004 and May 2006 for this cohort study. RESULTS: One hundred ninety two (89.7%) of 214 children met WHO ART initiation criteria based on clinical staging or CD4 cell count. Several low-cost measures identified individuals who met WHO ART initiation criteria to the following degree: WHO stages 3 or 4 had 87.5% (95% CI, 82.8-92.1) sensitivity and, by definition, 100% (CI, 100-100) specificity; WHO recommended advance disease TLC cutoffs: sensitivity = 23.9% (95% CI, 17.3-30.5) specificity = 78.2% (95% CI, 67.3-89.1). Low TLC was a common finding, (50 of 214; 23%); however, it did not improve the sensitivity or specificity of clinical staging in identifying the severely immunosuppressed stage 2 children. Growth failure or use of total lymphocyte counts in isolation were not reliable indicators of severe immunosuppression or need to initiate ART. CONCLUSION: The use of total lymphocyte count does not improve the ability to identify children in need of ART compared with clinical staging alone. Low absolute lymphocyte count did not correlate with severe immunosuppression based on CD4 cell count in this cohort.

Validation, performance under field conditions, and cost-effectiveness of Capillus HIV-1/HIV-2 and determine HIV-1/2 rapid human immunodeficiency virus antibody assays using sequential and parallel testing algorithms in Tanzania.

Rapid human immunodeficiency virus (HIV) antibody tests support the effort to expand access to HIV testing and counseling services in remote, rural, and poor parts of the world. We validated the Capillus HIV-1/HIV-2 (Trinity Biotech PLC, Bray, County Wicklow, Ireland) and Determine HIV-1/2 (Abbott Laboratories, Abbott Park, IL) rapid tests in a reference laboratory using patient samples from Tanzania and evaluated the performance of the tests under field conditions in northern Tanzania. We used the resulting data to study sequential and parallel testing algorithms. In the validation study, sensitivity, specificity, the predictive value of a positive test (PV(+)), and the predictive value of a negative test (PV(-)) were all 100% for Capillus and Determine. In the field evaluation among 12,737 clients, sensitivity, specificity, PV(+), and PV(-) were 99.7%, 99.8%, 98.7%, and 99.9%, respectively, for Capillus and 99.6%, 99.9%, 99.5%, and 99.9%, respectively, for Determine. A sequential testing algorithm that did not confirm a negative initial Capillus result with a Determine result cost $7.77 per HIV diagnosis but missed 0.3% of HIV infections. A sequential testing algorithm that did not confirm a negative initial Determine result with a Capillus result cost $7.64 per HIV diagnosis but missed 0.4% of HIV infections. A parallel testing algorithm cost $13.46 per HIV diagnosis but detected more HIV-infected clients.