Framework Programmable Platform for the Advanced Software Development Workstation: Preliminary system design document

The Framework Programmable Software Development Platform (FPP) is a project aimed at combining effective tool and data integration mechanisms with a model of the software development process in an intelligent integrated software environment. Guided by the model, this system development framework will take advantage of an integrated operating environment to automate effectively the management of the software development process so that costly mistakes during the development phase can be eliminated. The focus here is on the design of components that make up the FPP. These components serve as supporting systems for the Integration Mechanism and the Framework Processor and provide the 'glue' that ties the FPP together. Also discussed are the components that allow the platform to operate in a distributed, heterogeneous environment and to manage the development and evolution of software system artifacts

Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study.

The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts

Predictors and outcomes of Mycobacterium tuberculosis bacteremia among patients with HIV and tuberculosis co-infection enrolled in the ACTG A5221 STRIDE study

Background: We evaluated predictors and outcomes of Mycobacterium tuberculosis bacteremia among participants undergoing baseline mycobacterial blood culture in the ACTG A5221 STRIDE study, a randomized clinical trial comparing earlier with later ART among HIV-infected patients suspected of having tuberculosis with CD4-positive T-lymphocyte counts (CD4 counts) <250 cells/mm3. We conducted a secondary analysis comparing participants with respect to presence or absence of M. tuberculosis bacteremia. Methods: Participants with a baseline mycobacterial blood culture were compared with respect to the presence or absence of M. tuberculosis bacteremia. Baseline predictors of M. tuberculosis bacteremia were identified and participant outcomes were compared by mycobacteremia status. Results: Of 90 participants with baseline mycobacterial blood cultures, 29 (32.2%) were female, the median (IQR) age was 37 (31–45) years, CD4 count was 81 (33–131) cells/mm3, HIV-1 RNA level was 5.39 (4.96–5.83) log10 copies/mL, and 18 (20.0%) had blood cultures positive for M. tuberculosis. In multivariable analysis, lower CD4 count (OR 0.85 per 10-cell increase, p = 0.012), hemoglobin ≤8.5 g/dL (OR 5.8, p = 0.049), and confirmed tuberculosis (OR 17.4, p = 0.001) were associated with M. tuberculosis bacteremia. There were no significant differences in survival and AIDS-free survival, occurrence of tuberculosis immune reconstitution inflammatory syndrome (IRIS), or treatment interruption or discontinuation by M. tuberculosis bacteremia status. IRIS did not differ significantly between groups despite trends toward more virologic suppression and greater CD4 count increases at week 48 in the bacteremic group. Conclusions: Among HIV-infected tuberculosis suspects, lower CD4 count, hemoglobin ≤8.5 g/dL, and the presence of microbiologically confirmed pulmonary tuberculosis were associated with increased adjusted odds of mycobacteremia. No evidence of an association between M. tuberculosis bacteremia and the increased risk of IRIS was detected. Trial registration ClinicalTrials.gov: NCT00108862

Predictors and outcomes of Mycobacterium tuberculosis bacteremia among patients with HIV and tuberculosis co-infection enrolled in the ACTG A5221 STRIDE study.

BACKGROUND: We evaluated predictors and outcomes of Mycobacterium tuberculosis bacteremia among participants undergoing baseline mycobacterial blood culture in the ACTG A5221 STRIDE study, a randomized clinical trial comparing earlier with later ART among HIV-infected patients suspected of having tuberculosis with CD4-positive T-lymphocyte counts (CD4 counts)/mm(3). We conducted a secondary analysis comparing participants with respect to presence or absence of M. tuberculosis bacteremia. METHODS: Participants with a baseline mycobacterial blood culture were compared with respect to the presence or absence of M. tuberculosis bacteremia. Baseline predictors of M. tuberculosis bacteremia were identified and participant outcomes were compared by mycobacteremia status. RESULTS: Of 90 participants with baseline mycobacterial blood cultures, 29 (32.2%) were female, the median (IQR) age was 37 (31-45) years, CD4 count was 81 (33-131) cells/mm(3), HIV-1 RNA level was 5.39 (4.96-5.83) log10 copies/mL, and 18 (20.0%) had blood cultures positive for M. tuberculosis. In multivariable analysis, lower CD4 count (OR 0.85 per 10-cell increase, p = 0.012), hemoglobin ≤8.5 g/dL (OR 5.8, p = 0.049), and confirmed tuberculosis (OR 17.4, p = 0.001) were associated with M. tuberculosis bacteremia. There were no significant differences in survival and AIDS-free survival, occurrence of tuberculosis immune reconstitution inflammatory syndrome (IRIS), or treatment interruption or discontinuation by M. tuberculosis bacteremia status. IRIS did not differ significantly between groups despite trends toward more virologic suppression and greater CD4 count increases at week 48 in the bacteremic group. CONCLUSIONS: Among HIV-infected tuberculosis suspects, lower CD4 count, hemoglobin ≤8.5 g/dL, and the presence of microbiologically confirmed pulmonary tuberculosis were associated with increased adjusted odds of mycobacteremia. No evidence of an association between M. tuberculosis bacteremia and the increased risk of IRIS was detected. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00108862

Population-Based Incidence of Typhoid Fever in an Urban Informal Settlement and a Rural Area in Kenya: Implications for Typhoid Vaccine Use in Africa

Background: High rates of typhoid fever in children in urban settings in Asia have led to focus on childhood immunization in Asian cities, but not in Africa, where data, mostly from rural areas, have shown low disease incidence. We set out to compare incidence of typhoid fever in a densely populated urban slum and a rural community in Kenya, hypothesizing higher rates in the urban area, given crowding and suboptimal access to safe water, sanitation and hygiene. Methods: During 2007-9, we conducted population-based surveillance in Kibera, an urban informal settlement in Nairobi, and in Lwak, a rural area in western Kenya. Participants had free access to study clinics; field workers visited their homes biweekly to collect information about acute illnesses. In clinic, blood cultures were processed from patients with fever or pneumonia. Crude and adjusted incidence rates were calculated. Results: In the urban site, the overall crude incidence of Salmonella enterica serovar Typhi (S. Typhi) bacteremia was 247 cases per 100,000 person-years of observation (pyo) with highest rates in children 5–9 years old (596 per 100,000 pyo) and 2–4 years old (521 per 100,000 pyo). Crude overall incidence in Lwak was 29 cases per 100,000 pyo with low rates in children 2–4 and 5–9 years old (28 and 18 cases per 100,000 pyo, respectively). Adjusted incidence rates were highest in 2–4 year old urban children (2,243 per 100,000 pyo) which were.15-fold higher than rates in the rural site for the same age group

The Determinants of Activity and Specificity in Actinorhodin Type II Polyketide Ketoreductase

SummaryIn the actinorhodin type II polyketide synthase, the first polyketide modification is a regiospecific C9-carbonyl reduction, catalyzed by the ketoreductase (actKR). Our previous studies identified the actKR 94-PGG-96 motif as a determinant of stereospecificity. The molecular basis for reduction regiospecificity is, however, not well understood. In this study, we examined the activities of 20 actKR mutants through a combination of kinetic studies, PKS reconstitution, and structural analyses. Residues have been identified that are necessary for substrate interaction, and these observations have suggested a structural model for this reaction. Polyketides dock at the KR surface and are steered into the enzyme pocket where C7–C12 cyclization is mediated by the KR before C9-ketoreduction can occur. These molecular features can potentially serve as engineering targets for the biosynthesis of novel, reduced polyketides

Impact of socioeconomic deprivation on rate and cause of death in severe mental illness

Background: Socioeconomic status has important associations with disease-specific mortality in the general population. Although individuals with Severe Mental Illnesses (SMI) experience significant premature mortality, the relationship between socioeconomic status and mortality in this group remains under investigated.&lt;p&gt;&lt;/p&gt; Aims: To assess the impact of socioeconomic status on rate and cause of death in individuals with SMI (schizophrenia and bipolar disorder) relative to the local (Glasgow) and wider (Scottish) populations.&lt;p&gt;&lt;/p&gt; Methods: Cause and age of death during 2006-2010 inclusive for individuals with schizophrenia or bipolar disorder registered on the Glasgow Psychosis Clinical Information System (PsyCIS) were obtained by linkage to the Scottish General Register Office (GRO). Rate and cause of death by socioeconomic status, measured by Scottish Index of Multiple Deprivation (SIMD), were compared to the Glasgow and Scottish populations.&lt;p&gt;&lt;/p&gt; Results: Death rates were higher in people with SMI across all socioeconomic quintiles compared to the Glasgow and Scottish populations, and persisted when suicide was excluded. Differences were largest in the most deprived quintile (794.6 per 10,000 population vs. 274.7 and 252.4 for Glasgow and Scotland respectively). Cause of death varied by socioeconomic status. For those living in the most deprived quintile, higher drug-related deaths occurred in those with SMI compared to local Glasgow and wider Scottish population rates (12.3% vs. 5.9%, p = &#60;0.001 and 5.1% p = 0.002 respectively). A lower proportion of deaths due to cancer in those with SMI living in the most deprived quintile were also observed, relative to the local Glasgow and wider Scottish populations (12.3% vs. 25.1% p = 0.013 and 26.3% p = &#60;0.001). The proportion of suicides was significantly higher in those with SMI living in the more affluent quintiles relative to Glasgow and Scotland (54.6% vs. 5.8%, p = &#60;0.001 and 5.5%, p = &#60;0.001). Discussion and conclusions: Excess mortality in those with SMI occurred across all socioeconomic quintiles compared to the Glasgow and Scottish populations but was most marked in the most deprived quintiles when suicide was excluded as a cause of death. Further work assessing the impact of socioeconomic status on specific causes of premature mortality in SMI is needed

Epidemiology of Coxiella burnetii infection in Africa: a OneHealth systematic review

Background: Q fever is a common cause of febrile illness and community-acquired pneumonia in resource-limited settings. Coxiella burnetii, the causative pathogen, is transmitted among varied host species, but the epidemiology of the organism in Africa is poorly understood. We conducted a systematic review of C. burnetii epidemiology in Africa from a “One Health” perspective to synthesize the published data and identify knowledge gaps.&lt;p&gt;&lt;/p&gt; Methods/Principal Findings: We searched nine databases to identify articles relevant to four key aspects of C. burnetii epidemiology in human and animal populations in Africa: infection prevalence; disease incidence; transmission risk factors; and infection control efforts. We identified 929 unique articles, 100 of which remained after full-text review. Of these, 41 articles describing 51 studies qualified for data extraction. Animal seroprevalence studies revealed infection by C. burnetii (&#8804;13%) among cattle except for studies in Western and Middle Africa (18–55%). Small ruminant seroprevalence ranged from 11–33%. Human seroprevalence was &#60;8% with the exception of studies among children and in Egypt (10–32%). Close contact with camels and rural residence were associated with increased seropositivity among humans. C. burnetii infection has been associated with livestock abortion. In human cohort studies, Q fever accounted for 2–9% of febrile illness hospitalizations and 1–3% of infective endocarditis cases. We found no studies of disease incidence estimates or disease control efforts.&lt;p&gt;&lt;/p&gt; Conclusions/Significance: C. burnetii infection is detected in humans and in a wide range of animal species across Africa, but seroprevalence varies widely by species and location. Risk factors underlying this variability are poorly understood as is the role of C. burnetii in livestock abortion. Q fever consistently accounts for a notable proportion of undifferentiated human febrile illness and infective endocarditis in cohort studies, but incidence estimates are lacking. C. burnetii presents a real yet underappreciated threat to human and animal health throughout Africa.&lt;p&gt;&lt;/p&gt