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author:("banzi, S")
1.  Inflammation-mediated rheumatic diseases and atherosclerosis 
Annals of the Rheumatic Diseases  2000;59(5):321-325.
PMCID: PMC1753135  PMID: 10784507
2.  European Population Substructure Correlates with Systemic Lupus Erythematosus Endophenotypes in North Americans of European Descent 
Genes and immunity  2009;11(6):515-521.
Previous work has demonstrated that northern and southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. Here, 1855 SLE cases of European descent were genotyped for 4965 single nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished northern from southern European ancestry, PC2 differentiated eastern from western European ancestry, and PC3 delineated Ashkenazi Jewish ancestry. Compared to northern European ancestry, southern European ancestry was associated with autoantibody production (OR=1.40, 95% CI 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.
PMCID: PMC3951966  PMID: 19847193
Systemic lupus erythematosus; epidemiology; population substructure; genetics
3.  Breast Cancer in Systemic Lupus Erythematosus 
Oncology  2013;85(2):117-121.
Evidence points to a decreased breast cancer risk in systemic lupus erythematosus (SLE). We analyzed data from a large multisite SLE cohort, linked to cancer registries.
Information on age, SLE duration, cancer date, and histology was available. We analyzed information on histological type and performed multivariate logistic regression analyses of histological types according to age, SLE duration, and calendar year.
We studied 180 breast cancers in the SLE cohort. Of the 155 cases with histology information, 11 were referred to simply as ‘carcinoma not otherwise specified’. In the remaining 144 breast cancers, the most common histological type was ductal carcinoma (n = 95; 66%) followed by lobular adenocarcinoma (n = 11; 8%), 15 cancers were of mixed histology, and the remaining ones were special types. In our regression analyses, the independent risk factors for lobular versus ductal carcinoma was age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01–1.14] and for the ‘special’ subtypes it was age (OR 1.06, 95% CI 1.01–1.10) and SLE duration (OR 1.05, 95% CI 1.00–1.11).
Generally, up to 80% of breast cancers are ductal carcinomas. Though our results are not definitive, in the breast cancers that occur in SLE, there may be a slight decrease in the ductal histological type. In our analyses, age and SLE duration were independent predictors of histological status.
PMCID: PMC3934367  PMID: 23887245
Breast cancer; Systemic lupus erythematosus; Histopathology; Epidemiology
4.  Variability of Carbon and Water Fluxes Following Climate Extremes over a Tropical Forest in Southwestern Amazonia 
PLoS ONE  2014;9(2):e88130.
The carbon and water cycles for a southwestern Amazonian forest site were investigated using the longest time series of fluxes of CO2 and water vapor ever reported for this site. The period from 2004 to 2010 included two severe droughts (2005 and 2010) and a flooding year (2009). The effects of such climate extremes were detected in annual sums of fluxes as well as in other components of the carbon and water cycles, such as gross primary production and water use efficiency. Gap-filling and flux-partitioning were applied in order to fill gaps due to missing data, and errors analysis made it possible to infer the uncertainty on the carbon balance. Overall, the site was found to have a net carbon uptake of ≈5 t C ha−1 year−1, but the effects of the drought of 2005 were still noticed in 2006, when the climate disturbance caused the site to become a net source of carbon to the atmosphere. Different regions of the Amazon forest might respond differently to climate extremes due to differences in dry season length, annual precipitation, species compositions, albedo and soil type. Longer time series of fluxes measured over several locations are required to better characterize the effects of climate anomalies on the carbon and water balances for the whole Amazon region. Such valuable datasets can also be used to calibrate biogeochemical models and infer on future scenarios of the Amazon forest carbon balance under the influence of climate change.
PMCID: PMC3928111  PMID: 24558378
5.  Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus 
Nature genetics  2008;40(9):1062-1064.
The TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-κB–dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.
PMCID: PMC3897246  PMID: 19165919
6.  Integrated care as a means to improve primary care delivery for adults and adolescents in the developing world: a critical analysis of Integrated Management of Adolescent and Adult Illness (IMAI) 
BMC Medicine  2014;12:6.
More than three decades after the 1978 Declaration of Alma-Ata enshrined the goal of ‘health for all’, high-quality primary care services remain undelivered to the great majority of the world’s poor. This failure to effectively reach the most vulnerable populations has been, in part, a failure to develop and implement appropriate and effective primary care delivery models. This paper examines a root cause of these failures, namely that the inability to achieve clear and practical consensus around the scope and aims of primary care may be contributing to ongoing operational inertia. The present work also examines integrated models of care as a strategy to move beyond conceptual dissonance in primary care and toward implementation. Finally, this paper examines the strengths and weaknesses of a particular model, the World Health Organization’s Integrated Management of Adolescent and Adult Illness (IMAI), and its potential as a guidepost toward improving the quality of primary care delivery in poor settings.
Integration and integrated care may be an important approach in establishing a new paradigm of primary care delivery, though overall, current evidence is mixed. However, a number of successful specific examples illustrate the potential for clinical and service integration to positively impact patient care in primary care settings. One example deserving of further examination is the IMAI, developed by the World Health Organization as an operational model that integrates discrete vertical interventions into a comprehensive delivery system encompassing triage and screening, basic acute and chronic disease care, basic prevention and treatment services, and follow-up and referral guidelines. IMAI is an integrated model delivered at a single point-of-care using a standard approach to each patient based on the universal patient history and physical examination. The evidence base on IMAI is currently weak, but whether or not IMAI itself ultimately proves useful in advancing primary care delivery, it is these principles that should serve as the basis for developing a standard of integrated primary care delivery for adults and adolescents that can serve as the foundation for ongoing quality improvement.
As integrated primary care is the standard of care in the developed world, so too must we move toward implementing integrated models of primary care delivery in poorer settings. Models such as IMAI are an important first step in this evolution. A robust and sustained commitment to innovation, research and quality improvement will be required if integrated primary care delivery is to become a reality in developing world.
PMCID: PMC3895758  PMID: 24423387
Primary care; Integrated management; Integration; Quality improvement; Health care delivery; Health systems; IMAI
8.  Comparative cost models of a liquid nitrogen vapor phase (LNVP) cold chain-distributed cryopreserved malaria vaccine vs. a conventional vaccine 
Vaccine  2012;31(2):380-386.
Typically, vaccines distributed through the Expanded Program on Immunization (EPI) use a 2–8 °C cold chain with 4–5 stops. The PfSPZ Vaccine comprises whole live-attenuated cryopreserved sporozoites stored in liquid nitrogen (LN2) vapor phase (LNVP) below −140 °C and would be distributed through a LNVP cold chain. The purpose of this study was to model LNVP cold chain distribution for the cryopreserved PfSPZ Vaccine in Tanzania, estimate the costs and compare these costs to those that would be incurred in distributing a ‘conventional’ malaria vaccine through the EPI. Capital and recurrent costs for storage, transportation, labor, energy usage and facilities were determined for the birth cohort in Tanzania over five years. Costs were calculated using WHO/UNESCO calculators. These were applied to a 2–8 °C distribution model with national, regional, district, and health facility levels, and for the cryopreserved vaccine using a ‘modified hub-and-spoke’ (MH-S) LNVP distribution system comprising a central national store, peripheral health facilities and an intermediate district-level transhipment stop. Estimated costs per fully immunized child (FIC) were $ 6.11 for the LNVP-distributed cryopreserved vaccine where the LN2 is generated, and $ 6.04 with purchased LN2 (assuming US $ 1.00/L). The FIC costs for distributing a conventional vaccine using the four level 2–8 °C cold chain were $ 6.10, and with a tariff distribution system as occurs in Tanzania the FIC cost was $ 5.53. The models, therefore, predicted little difference in 5-year distribution costs between the PfSPZ Vaccine distributed through a MH-S LNVP cold chain and a conventional vaccine distributed through the more traditional EPI system. A LNVP cold chain provides additional benefits through the use of durable dry shippers because no refrigerators, freezers or refrigerated trucks are required. Thus strain at the cold chain periphery, vaccine wastage from cold chain failures and the environmental impact of distribution would all be reduced.
PMCID: PMC3666854  PMID: 23146676
Vaccine; Cold chain; Liquid nitrogen vapor phase; Malaria; Distribution cost; Model
9.  Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma 
Hepatocellular carcinoma (HCC) represents a global health problem. Infections with hepatitis B or C virus, non-alcoholic steatohepatitis disease, alcohol abuse, or dietary exposure to aflatoxin are the major risk factors to the development of this tumor. Regardless of the carcinogenic insult, HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis. Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity for β-galactosides and conserved sequence motifs. Here, we summarize the current literature implicating galectins in the pathogenesis of HCC. Expression of “proto-type” galectin-1, “chimera-type” galectin-3 and “tandem repeat-type” galectin-4 is up-regulated in HCC cells compared to their normal counterparts. On the other hand, the “tandem-repeat-type” lectins galectin-8 and galectin-9 are down-regulated in tumor hepatocytes. The abnormal expression of these galectins correlates with tumor growth, HCC cell migration and invasion, tumor aggressiveness, metastasis, postoperative recurrence and poor prognosis. Moreover, these galectins have important roles in other pathological conditions of the liver, where chronic inflammation and/or fibrosis take place. Galectin-based therapies have been proposed to attenuate liver pathologies. Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC.
PMCID: PMC3870534  PMID: 24379606
Galectins; Hepatocellular carcinoma; Inflammation-associated liver injury; Hepatitis B or C virus infection-associated hepatocellular carcinoma; Fibrosis-related liver pathologies
10.  Baseline assessment of adult and adolescent primary care delivery in Rwanda: an opportunity for quality improvement 
As resource-limited health systems evolve to address complex diseases, attention must be returned to basic primary care delivery. Limited data exists detailing the quality of general adult and adolescent primary care delivered at front-line facilities in these regions. Here we describe the baseline quality of care for adults and adolescents in rural Rwanda.
Patients aged 13 and older presenting to eight rural health center outpatient departments in one district in southeastern Rwanda between February and March 2011 were included. Routine nurse-delivered care was observed by clinical mentors trained in the WHO Integrated Management of Adolescent & Adult Illness (IMAI) protocol using standardized checklists, and compared to decisions made by the clinical mentor as the gold standard.
Four hundred and seventy consultations were observed. Of these, only 1.5% were screened and triaged for emergency conditions. Fewer than 10% of patients were routinely screened for chronic conditions including HIV, tuberculosis, anemia or malnutrition. Nurses correctly diagnosed 50.1% of patient complaints (95% CI: 45.7%-54.5%) and determined the correct treatment 44.9% of the time (95% CI: 40.6%-49.3%). Correct diagnosis and treatment varied significantly across health centers (p = 0.03 and p = 0.04, respectively).
Fundamental gaps exist in adult and adolescent primary care delivery in Rwanda, including triage, screening, diagnosis, and treatment, with significant variability across conditions and facilities. Research and innovation toward improving and standardizing primary care delivery in sub-Saharan Africa is required. IMAI, supported by routine mentorship, is one potentially important approach to establishing the standards necessary for high-quality care.
PMCID: PMC3878570  PMID: 24344805
Primary care; Africa; Resource-limited settings; Quality improvement; Training; Integration; IMAI; Outpatient department; Nurses
11.  Environmental Contaminants in Hospital Settings and Progress in Disinfecting Techniques 
BioMed Research International  2013;2013:429780.
Medical devices, such as stethoscopes, and other objects found in hospital, such as computer keyboards and telephone handsets, may be reservoirs of bacteria for healthcare-associated infections. In this cross-over study involving an Italian teaching hospital we evaluated microbial contamination (total bacterial count (TBC) at 36°C/22°C, Staphylococcus spp., moulds, Enterococcus spp., Pseudomonas spp., E. coli, total coliform bacteria, Acinetobacter spp., and Clostridium difficile) of these devices before and after cleaning and differences in contamination between hospital units and between stethoscopes and keyboards plus handsets. We analysed 37 telephone handsets, 27 computer keyboards, and 35 stethoscopes, comparing their contamination in four hospital units. Wilcoxon signed-rank and Mann-Whitney tests were used. Before cleaning, many samples were positive for Staphylococcus spp. and coliforms. After cleaning, CFUs decreased to zero in most comparisons. The first aid unit had the highest and intensive care the lowest contamination (P < 0.01). Keyboards and handsets had higher TBC at 22°C (P = 0.046) and mould contamination (P = 0.002) than stethoscopes. Healthcare professionals should disinfect stethoscopes and other possible sources of bacterial healthcare-associated infections. The cleaning technique used was effective in reducing bacterial contamination. Units with high patient turnover, such as first aid, should practise stricter hygiene.
PMCID: PMC3830765  PMID: 24286078
12.  Beyond antimalarial stock-outs: implications of health provider compliance on out-of-pocket expenditure during care-seeking for fever in South East Tanzania 
To better understand how stock-outs of the first line antimalarial, Artemisinin-based Combination Therapy (ACT) and other non-compliant health worker behaviour, influence household expenditures during care-seeking for fever in the Ulanga District in Tanzania.
We combined weekly ACT stock data for the period 2009-2011 from six health facilities in the Ulanga District in Tanzania, together with household data from 333 respondents on the cost of fever care-seeking in Ulanga during the same time period to establish how health seeking behaviour and expenditure might vary depending on ACT availability in their nearest health facility.
Irrespective of ACT stock-outs, more than half (58%) of respondents sought initial care in the public sector, the remainder seeking care in the private sector where expenditure was higher by 19%. Over half (54%) of respondents who went to the public sector reported incidences of non-compliant behaviour by the attending health worker (e.g. charging those who were eligible for free service or referring patients to the private sector despite ACT stock), which increased household expenditure per fever episode from USD0.14 to USD1.76. ACT stock-outs were considered to be the result of non-compliant behaviour of others in the health system and increased household expenditure by 21%; however we lacked sufficient statistical power to confirm this finding.
System design and governance challenges in the Tanzanian health system have resulted in numerous ACT stock-outs and frequent non-compliant public sector health worker behaviour, both of which increase out-of-pocket health expenditure. Interventions are urgently needed to ensure a stable supply of ACT in the public sector and increase health worker accountability.
PMCID: PMC3815072  PMID: 24161029
Health worker behaviour; Informal charges; Stock-outs; Antimalarial; Tanzania
13.  SF-36 summary and subscale scores are reliable outcomes of neuropsychiatric events in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(6):961-967.
To examine change in health-related quality of life (HRQoL) in association with clinical outcomes of neuropsychiatric (NP) events in SLE.
An international study evaluated newly diagnosed SLE patients for NP events attributed to SLE and non-SLE causes. Outcome of events was determined by physician-completed 7-point scale and compared to patient-completed SF-36 questionnaires. Statistical analysis used linear mixed-effects regression models with patient specific random effects.
274 patients (92% female; 68% Caucasian), from a cohort of 1400, had ≥ 1 NP event where the interval between assessments was 12.3 ± 2 months. The overall difference in change between visits in mental component summary (MCS) scores of the SF-36 was significant (p<0.0001) following adjustments for gender, ethnicity, center and previous score. A consistent improvement in NP status (N=295) was associated with an increase in the mean(SD) adjusted MCS score of 3.66(0.89) in SF-36 scores. Between paired visits where NP status consistently deteriorated (N=30), the adjusted MCS score decreased by 4.00(1.96). For the physical component summary (PCS) scores the corresponding changes were +1.73(0.71) and −0.62(1.58) (p<0.05) respectively. Changes in SF-36 subscales were in the same direction (p<0.05; with the exception of role physical). Sensitivity analyses confirmed these findings. Adjustment for age, education, medications, SLE disease activity, organ damage, disease duration, attribution and characteristics of NP events did not substantially alter the results.
Changes in SF-36 summary and subscale scores, in particular those related to mental health, are strongly associated with the clinical outcome of NP events in SLE patients.
PMCID: PMC3795436  PMID: 21342917
Systemic lupus erythematosus; Neuropsychiatric; Inception cohort; Health related quality of life; SF-36
14.  Obstetric Fistula in Burundi: a comprehensive approach to managing women with this neglected disease 
In Burundi, the annual incidence of obstetric fistula is estimated to be 0.2-0.5% of all deliveries, with 1000–2000 new cases per year. Despite this relatively high incidence, national capacity for identifying and managing obstetric fistula is very limited. Thus, in July 2010, Medecins Sans Frontieres (MSF) set up a specialised Obstetric Fistula Centre in Gitega (Gitega Fistula Centre, GFC), the only permanent referral centre for obstetric fistula in Burundi. A comprehensive model of care is offered including psychosocial support, conservative and surgical management, post-operative care and follow-up. We describe this model of care, patient outcomes and the operational challenges.
Descriptive study using routine programme data.
Between July 2010 and December 2011, 470 women with obstetric fistula presented for the first time at GFC, of whom 458 (98%) received treatment. Early urinary catheterization (conservative management) was successful in four out of 35 (11%) women. Of 454 (99%) women requiring surgical management, 394 (87%) were discharged with a closed fistula, of whom 301 (76%) were continent of urine and/or faeces, while 93 (24%) remained incontinent of urine and/or faeces. In 59 (13%) cases, the fistula was complex and could not be closed. Outcome status was unknown for one woman. Median duration of stay at GFC was 39 days (Interquartile range IQR, 31–51 days).
The main operational challenges included: i) early case finding and recruitment for conservative management, ii) national capacity building in obstetric fistula surgical repair, and iii) assessing the psychosocial impact of this model.
In a rural African setting, it is feasible to implement a comprehensive package of fistula care using a dedicated fistula facility, and satisfactory surgical repair outcomes can be achieved. Several operational challenges are discussed.
PMCID: PMC3765123  PMID: 23965150
Obstetric fistula; Comprehensive management; Operational research; Burundi
No new drugs have been approved for the treatment of systemic lupus erythematosus (SLE) by the FDA for the last 30 years and one barrier has been the lack of validated of biomarkers and surrogate endpoints. Validation of SLE biomarkers in the past have been methodologically flawed. We put forth a conceptual framework and the five critical criterion for validating putative biomarkers and bio-surrogates in this heterogeneous multi-system disease with protean manifestations. Using the example of a putative biomarker for end-stage renal disease from lupus nephritis, we also performed computer simulations for planning a biomarker bio-repository to support the validation process. “Random time window” sampling where a biomarker is obtained in an interval randomly selected from the total follow-up time for that subject yields serious ‘survival bias’. This can be avoided by the “fixed calendar window” design, in which biomarkers are measured within the same, pre-specified period for all cohort members who remain at risk during that period. In lupus nephritis where the incidence rate of end-stage renal disease is relatively low, to accumulate 300 instances of end-stage renal disease, at risk patients would have to be followed for about 5,000 person-years, implying 500 subjects followed, on average, for about 10 years. Increasing the number of biomarker determinations per subject from one to five reduces the required number of subjects by 10-15%, while further increases of the number of observations per subject yielded much smaller gains. The large numbers of subjects required for a bio-repository, makes it essential to maximize the efficiency of study designs and analyses and provides the strongest rationale for collaboration and the use of standardized measures to ensure comparability.
PMCID: PMC3746003  PMID: 19275685
16.  Derivation and Validation of Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic Lupus Erythematosus 
Arthritis and rheumatism  2012;64(8):2677-2686.
The Systemic Lupus Collaborating Clinics (SLICC) revised and validated the American College of Rheumatology (ACR) SLE classification criteria in order to improve clinical relevance, meet stringent methodology requirements and incorporate new knowledge in SLE immunology.
The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. SLICC validated the classification criteria in a new validation sample of 690 SLE patients and controls.
Seventeen criteria were identified. The SLICC criteria for SLE classification requires: 1) Fulfillment of at least four criteria, with at least one clinical criterion AND one immunologic criterion OR 2) Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications than the current ACR classification criteria (49 versus 70, p=0.0082), had greater sensitivity (94% versus 86%, p<0.0001) and equal specificity (92% versus 93%, p=0.39). In the validation set, the SLICC Classification criteria resulted in fewer misclassifications (62 versus 74, p=0.24), had greater sensitivity (97% versus 83%, p<0.0001) but less specificity (84% versus 96%, p<0.0001).
The new SLICC classification criteria performed well on a large set of patient scenarios rated by experts. They require that at least one clinical criterion and one immunologic criterion be present for a classification of SLE. Biopsy confirmed nephritis compatible with lupus (in the presence of SLE autoantibodies) is sufficient for classification.
PMCID: PMC3409311  PMID: 22553077
17.  Biomarkers in systemic lupus erythematosus: challenges and prospects for the future 
The search for lupus biomarkers to diagnose, monitor, stratify, and predict individual response to therapy is currently more intense than ever before. This effort is essential for several reasons. First, epidemic overdiagnosis and underdiagnosis of lupus, even by certified rheumatologists, leads to errors in therapy with concomitant side effects which may be more serious than the disease itself. Second, identification of lupus flares remains as much an art as it is a science. Third, the capacity to stratify patients so as to predict those who will develop specific patterns of organ involvement is not currently possible but would potentially lead to preventive therapeutic strategies. Fourth, only one new drug for the treatment of lupus has been approved by the US Food and Drug Administration in over 50 years. A major obstacle in this pipeline is the dearth of biomarkers available to prove a patient has responded to an experimental therapeutic intervention. This review will summarize the challenges faced in the discovery and validation of lupus biomarkers, the most promising lupus biomarkers identified to date, and the promise of future directions.
PMCID: PMC3728979  PMID: 23904865
biomarker; lupus; systemic lupus erythematosus; SLE
18.  The Tanzania Connect Project: a cluster-randomized trial of the child survival impact of adding paid community health workers to an existing facility-focused health system 
BMC Health Services Research  2013;13(Suppl 2):S6.
Tanzania has been a pioneer in establishing community-level services, yet challenges remain in sustaining these systems and ensuring adequate human resource strategies. In particular, the added value of a cadre of professional community health workers is under debate. While Tanzania has the highest density of primary health care facilities in Africa, equitable access and quality of care remain a challenge. Utilization for many services proven to reduce child and maternal mortality is unacceptably low. Tanzanian policy initiatives have sought to address these problems by proposing expansion of community-based providers, but the Ministry of Health and Social Welfare (MoHSW ) lacks evidence that this merits national implementation. The Tanzania Connect Project is a randomized cluster trial located in three rural districts with a population of roughly 360,000 ( Kilombero, Rufiji, and Ulanga).
Description of intervention
Connect aims to test whether introducing a community health worker into a general program of health systems strengthening and referral improvement will reduce child mortality, improve access to services, expand utilization, and alter reproductive, maternal, newborn and child health seeking behavior; thereby accelerating progress towards Millennium Development Goals 4 and 5. Connect has introduced a new cadre — Community Health Agents (CHA) — who were recruited from and work in their communities. To support the CHA, Connect developed supervisory systems, launched information and monitoring operations, and implemented logistics support for integration with existing district and village operations. In addition, Connect’s district-wide emergency referral strengthening intervention includes clinical and operational improvements.
Evaluation design
Designed as a community-based cluster-randomized trial, CHA were randomly assigned to 50 of the 101 villages within the Health and Demographic Surveillance System (HDSS) in the three study districts. To garner detailed information on household characteristics, behaviors, and service exposure, a random sub-sample survey of 3,300 women of reproductive age will be conducted at the baseline and endline. The referral system intervention will use baseline, midline, and endline facility-based data to assess systemic changes. Implementation and impact research of Connect will assess whether and how the presence of the CHA at village level provides added life-saving value to the health system.
Global commitment to launching community-based primary health care has accelerated in recent years, with much of the implementation focused on Africa. Despite extensive investment, no program has been guided by a truly experimental study. Connect will not only address Tanzania’s need for policy and operational research, it will bridge a critical international knowledge gap concerning the added value of salaried professional community health workers in the context of a high density of fixed facilities.
Trial registration: ISRCTN96819844
PMCID: PMC3668255  PMID: 23819587
19.  Approaches to ensuring and improving quality in the context of health system strengthening: a cross-site analysis of the five African Health Initiative Partnership programs 
BMC Health Services Research  2013;13(Suppl 2):S8.
Integrated into the work in health systems strengthening (HSS) is a growing focus on the importance of ensuring quality of the services delivered and systems which support them. Understanding how to define and measure quality in the different key World Health Organization building blocks is critical to providing the information needed to address gaps and identify models for replication.
Description of approaches
We describe the approaches to defining and improving quality across the five country programs funded through the Doris Duke Charitable Foundation African Health Initiative. While each program has independently developed and implemented country-specific approaches to strengthening health systems, they all included quality of services and systems as a core principle. We describe the differences and similarities across the programs in defining and improving quality as an embedded process essential for HSS to achieve the goal of improved population health. The programs measured quality across most or all of the six WHO building blocks, with specific areas of overlap in improving quality falling into four main categories: 1) defining and measuring quality; 2) ensuring data quality, and building capacity for data use for decision making and response to quality measurements; 3) strengthened supportive supervision and/or mentoring; and 4) operational research to understand the factors associated with observed variation in quality.
Learning the value and challenges of these approaches to measuring and improving quality across the key components of HSS as the projects continue their work will help inform similar efforts both now and in the future to ensure quality across the critical components of a health system and the impact on population health.
PMCID: PMC3668288  PMID: 23819662
20.  Dietary ω-3 Polyunsaturated Fatty Acid DHA: A Potential Adjuvant in the Treatment of Cancer 
BioMed Research International  2013;2013:310186.
ω-3 Polyunsaturated fatty acids (PUFAs), mainly present in fish oil, are part of the human diet. Among PUFAs, docosahexaenoic acid (DHA) has received particular attention for its anti-inflammatory, antiproliferative, proapoptotic, antiangiogenetic, anti-invasion, and antimetastatic properties. These data suggest that DHA can exert antitumor activity potentially representing an effective adjuvant in cancer chemotherapy. This review is focused on current knowledge supporting the potential use of DHA for the enhancement of the efficacy of anticancer treatments in relation to its ability to enhance the uptake of anticancer drugs, regulate the oxidative status of tumor cells, and inhibit tumor cell invasion and metastasis.
PMCID: PMC3676987  PMID: 23762838
21.  Acupuncture for systemic lupus erythematosus: a pilot RCT feasibility and safety study 
Lupus  2008;17(12):1108-1116.
The objective of this study was to determine the feasibility of studying acupuncture in patients with systemic lupus erythematosus (SLE), and to pilot test the safety and explore benefits of a standardized acupuncture protocol designed to reduce pain and fatigue. Twenty-four patients with SLE were randomly assigned to receive 10 sessions of either acupuncture, minimal needling or usual care. Pain, fatigue and SLE disease activity were assessed at baseline and following the last sessions. Safety was assessed at each session. Fifty-two patients were screened to enroll 24 eligible and interested persons. Although transient side effects, such as brief needling pain and lightheadedness, were reported, no serious adverse events were associated with either the acupuncture or minimal needling procedures. Twenty-two participants completed the study, and the majority (85%) of acupuncture and minimal needling participants were able to complete their sessions within the specified time period of 5–6 weeks. 40% of patients who received acupuncture or minimal needling had ≥30% improvement on standard measures of pain, but no usual care patients showed improvement in pain. A ten-session course of acupuncture appears feasible and safe for patients with SLE. Benefits were similar for acupuncture and minimal needling.
PMCID: PMC3633212  PMID: 19029279
acupuncture; pain; randomized controlled trial; systemic lupus erythematosus
22.  Association Between Depression and Vascular Disease in Systemic Lupus Erythematosus 
The Journal of rheumatology  2011;39(2):262-268.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with increased prevalence of cardiovascular disease (CVD) and depression. Although depression may contribute to CVD risk in population-based studies, its influence on cardiovascular morbidity in SLE has not been evaluated. We evaluated the association between depression and vascular disease in SLE.
A cross-sectional study was conducted from 2002–2005 in 161 women with SLE and without CVD. The primary outcome measure was a composite vascular disease marker consisting of the presence of coronary artery calcium and/or carotid artery plaque.
In total, 101 women met criteria for vascular disease. In unadjusted analyses, several traditional cardiovascular risk factors, inflammatory markers, adiposity, SLE disease-related factors, and depression were associated with vascular disease. In the final multivariable model, the psychological variable depression was associated with nearly 4-fold higher odds for vascular disease (OR 3.85, 95% CI 1.37, 10.87) when adjusted for other risk factors of age, lower education level, hypertensive status, waist-hip ratio, and C-reactive protein.
In SLE, depression is independently associated with vascular disease, along with physical factors.
PMCID: PMC3632335  PMID: 22174200
23.  Pharmacointeraction Network Models Predict Unknown Drug-Drug Interactions 
PLoS ONE  2013;8(4):e61468.
Drug-drug interactions (DDIs) can lead to serious and potentially lethal adverse events. In recent years, several drugs have been withdrawn from the market due to interaction-related adverse events (AEs). Current methods for detecting DDIs rely on the accumulation of sufficient clinical evidence in the post-market stage – a lengthy process that often takes years, during which time numerous patients may suffer from the adverse effects of the DDI. Detection methods are further hindered by the extremely large combinatoric space of possible drug-drug-AE combinations. There is therefore a practical need for predictive tools that can identify potential DDIs years in advance, enabling drug safety professionals to better prioritize their limited investigative resources and take appropriate regulatory action. To meet this need, we describe Predictive Pharmacointeraction Networks (PPINs) – a novel approach that predicts unknown DDIs by exploiting the network structure of all known DDIs, together with other intrinsic and taxonomic properties of drugs and AEs. We constructed an 856-drug DDI network from a 2009 snapshot of a widely-used drug safety database, and used it to develop PPIN models for predicting future DDIs. We compared the DDIs predicted based solely on these 2009 data, with newly reported DDIs that appeared in a 2012 snapshot of the same database. Using a standard multivariate approach to combine predictors, the PPIN model achieved an AUROC (area under the receiver operating characteristic curve) of 0.81 with a sensitivity of 48% given a specificity of 90%. An analysis of DDIs by severity level revealed that the model was most effective for predicting “contraindicated” DDIs (AUROC = 0.92) and less effective for “minor” DDIs (AUROC = 0.63). These results indicate that network based methods can be useful for predicting unknown drug-drug interactions.
PMCID: PMC3631217  PMID: 23620757
24.  Development of a Scalable Pharmacogenomic Clinical Decision Support Service 
Advances in sequencing technology are making genomic data more accessible within the healthcare environment. Published pharmacogenetic guidelines attempt to provide a clinical context for specific genomic variants; however, the actual implementation to convert genomic data into a clinical report integrated within an electronic medical record system is a major challenge for any hospital. We created a two-part solution that integrates with the medical record system and converts genetic variant results into an interpreted clinical report based on published guidelines. We successfully developed a scalable infrastructure to support TPMT genetic testing and are currently testing approximately two individuals per week in our production version. We plan to release an online variant to clinical interpretation reporting system in order to facilitate translation of pharmacogenetic information into clinical practice.
PMCID: PMC3814487  PMID: 24303299
25.  Metabolomics as a Tool to Investigate Abiotic Stress Tolerance in Plants 
Metabolites reflect the integration of gene expression, protein interaction and other different regulatory processes and are therefore closer to the phenotype than mRNA transcripts or proteins alone. Amongst all –omics technologies, metabolomics is the most transversal and can be applied to different organisms with little or no modifications. It has been successfully applied to the study of molecular phenotypes of plants in response to abiotic stress in order to find particular patterns associated to stress tolerance. These studies have highlighted the essential involvement of primary metabolites: sugars, amino acids and Krebs cycle intermediates as direct markers of photosynthetic dysfunction as well as effectors of osmotic readjustment. On the contrary, secondary metabolites are more specific of genera and species and respond to particular stress conditions as antioxidants, Reactive Oxygen Species (ROS) scavengers, coenzymes, UV and excess radiation screen and also as regulatory molecules. In addition, the induction of secondary metabolites by several abiotic stress conditions could also be an effective mechanism of cross-protection against biotic threats, providing a link between abiotic and biotic stress responses. Moreover, the presence/absence and relative accumulation of certain metabolites along with gene expression data provides accurate markers (mQTL or MWAS) for tolerant crop selection in breeding programs.
PMCID: PMC3634444  PMID: 23455464
cold; heat; metabolite profiling; mQTL; omics; osmoprotectants; oxidative stress; salt stress; soil flooding; water stress

Results 1-25 (102)