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Background: Congenital heart disease (CHD) is the most common congenital anomaly. Almost 90% of isolated cases have an unexplained genetic etiology after clinical testing. Non-canonical splice variants that disrupt mRNA splicing through the loss or creation of exon boundaries are not routinely captured and/or evaluated by standard clinical genetic tests. Recent computational algorithms such as SpliceAI have shown an ability to predict such variants, but are not specific to cardiac-expressed genes and transcriptional isoforms., Methods: We used genome sequencing (GS) (n = 1101 CHD probands) and myocardial RNA-Sequencing (RNA-Seq) (n = 154 CHD and n = 43 cardiomyopathy probands) to identify and validate splice disrupting variants, and to develop a heart-specific model for canonical and non-canonical splice variants that can be applied to patients with CHD and cardiomyopathy. Two thousand five hundred seventy GS samples from the Medical Genome Reference Bank were analyzed as healthy controls., Results: Of 8583 rare DNA splice-disrupting variants initially identified using SpliceAI, 100 were associated with altered splice junctions in the corresponding patient myocardium affecting 95 genes. Using strength of myocardial gene expression and genome-wide DNA variant features that were confirmed to affect splicing in myocardial RNA, we trained a machine learning model for predicting cardiac-specific splice-disrupting variants (AUC 0.86 on internal validation). In a validation set of 48 CHD probands, the cardiac-specific model outperformed a SpliceAI model alone (AUC 0.94 vs 0.67 respectively). Application of this model to an additional 947 CHD probands with only GS data identified 1% patients with canonical and 11% patients with non-canonical splice-disrupting variants in CHD genes. Forty-nine percent of predicted splice-disrupting variants were intronic and > 10 bp from existing splice junctions. The burden of high-confidence splice-disrupting variants in CHD genes was 1.28-fold higher in CHD cases compared with healthy controls., Conclusions: A new cardiac-specific in silico model was developed using complementary GS and RNA-Seq data that improved genetic yield by identifying a significant burden of non-canonical splice variants associated with CHD that would not be detectable through panel or exome sequencing., (© 2024. The Author(s).)

Background: Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis, prognosis, and management of brain tumors. Our objective is to validate four plasma biomarkers - glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloprotease 3 (MMP3) and fatty acid binding protein 4 (FABP4) - and compare them with established brain tumor molecular markers and survival., Methods: Our cohort consisted of patients with benign and malignant brain tumors (GBM = 77, Astrocytomas = 26, Oligodendrogliomas = 23, Secondary tumors = 35, Meningiomas = 70, Schwannomas = 15, Pituitary adenomas = 15, Normal individuals = 30). For measurements, we used ultrasensitive electrochemiluminescence multiplexed immunoassays., Results: High plasma GFAP concentration was associated with GBM, low GFAP and high FABP4 were associated with meningiomas, and low GFAP and low FABP4 were associated with astrocytomas and oligodendrogliomas. NEFL was associated with progression of disease. Several prognostic genetic alterations were significantly associated with all plasma biomarker levels. We found no independent associations between plasma GFAP, NEFL, FABP4 and MMP3, and overall survival. The candidate biomarkers could not reliably discriminate GBM from primary or secondary CNS lymphomas., Conclusions: GFAP, NEFL, FABP4 and MMP3 are useful for differential diagnosis and prognosis, and are associated with molecular changes in gliomas., (© 2024. The Author(s).)

Background: Antibiotics remain the primary treatment for community acquired pneumonia (CAP), however rising rates of antimicrobial resistance may jeopardize their future efficacy. With higher rates of disease reported in the youngest populations, effective treatment courses for pediatric pneumonia are of paramount importance. This study is the first to examine the quality of pediatric antibiotic use by agent, dose and duration., Methods: A retrospective cohort study included all outpatient/primary care physician visits for pediatric CAP (aged < 19 years) between January 1 2014 to December 31 2018. Relevant practice guidelines were identified, and treatment recommendations extracted. Amoxicillin was the primary first-line agent for pediatric CAP. Categories of prescribing included: guideline adherent, effective but unnecessary (excess dose and/or duration), under treatment (insufficient dose and/or duration), and not recommended. Proportions of attributable-antibiotic use were examined by prescribing category, and then stratified by age and sex., Result(s): A total of 42,452 episodes of pediatric CAP were identified. Of those, 31,347 (76%) resulted in an antibiotic prescription. Amoxicillin accounted for 51% of all prescriptions. Overall, 27% of prescribing was fully guideline adherent, 19% effective but unnecessary, 10% under treatment, and 44% not recommended by agent. Excessive duration was the hallmark of effective but unnecessary prescribing (97%) Macrolides accounted for the majority on non-first line agent use, with only 32% of not recommended prescribing preceded by a previous course of antibiotics., Conclusion(s): This study is the first in Canada to examine prescribing quality for pediatric CAP by agent, dose and duration. Utilizing first-line agents, and shorter-course treatments are targets for stewardship., (© 2023. The Author(s).)

Background: Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study., Methods: Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported., Results: Of 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population., Conclusions: Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure., Trial Registration: NCT02049138., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To obtain updated estimates of the incidence and prevalence of neurofibromatosis type 1 (NF1) and type 2 (NF2)., Study Design: We conducted a systematic search of NF1 and NF2 incidence or prevalence studies, in OVID Medline, OVID Embase, Web of Science, and Cinahl. Studies were appraised with the Joanna Briggs Institute Prevalence Critical Appraisal tool. Pooled incidence and prevalence rates were estimated through random-effects meta-analysis., Results: From 1,939 abstracts, 20 studies were fully appraised and 12 were included in the final review. Pooled NF1 prevalence was 1 in 3,164 (95%CI: 1 in 2,132-1 in 4,712). This was higher in studies that screened for NF1, compared to identification of NF1 through medical records (1 in 2,020 and 1 in 4,329, respectively). NF1 pooled birth incidence was 1 in 2,662 (95%CI: 1 in 1,968-1 in 3,601). There were only 2 studies on NF2 prevalence, so data were not pooled. Pooled NF2 birth incidence was 1.08 per 50,000 births (95%CI: 1 in 32,829-1 in 65,019)., Conclusion: We present updated estimates of the incidence and prevalence of NF1 and NF2, to help plan for healthcare access and allocation. The prevalence of NF1 from screening studies is higher than from medical record studies, suggesting that the disease may be under recognized. More studies are needed regarding the prevalence of NF2., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Background: Acute kidney injury (AKI) and blackwater fever (BWF) are related but distinct renal complications of acute febrile illness in East Africa. The pathogenesis and prognostic significance of BWF and AKI are not well understood., Methods: A prospective observational cohort study was conducted to evaluate the association between BWF and AKI in children hospitalized with an acute febrile illness. Secondary objectives were to examine the association of AKI and BWF with (i) host response biomarkers and (ii) mortality. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria and BWF was based on parental report of tea-colored urine. Host markers of immune and endothelial activation were quantified on admission plasma samples. The relationships between BWF and AKI and clinical and biologic factors were evaluated using multivariable regression., Results: We evaluated BWF and AKI in 999 children with acute febrile illness (mean age 1.7 years (standard deviation 1.06), 55.7% male). At enrollment, 8.2% of children had a history of BWF, 49.5% had AKI, and 11.1% had severe AKI. A history of BWF was independently associated with 2.18-fold increased odds of AKI (95% CI 1.15 to 4.16). When examining host response, severe AKI was associated with increased immune and endothelial activation (increased CHI3L1, sTNFR1, sTREM-1, IL-8, Angpt-2, sFlt-1) while BWF was predominantly associated with endothelial activation (increased Angpt-2 and sFlt-1, decreased Angpt-1). The presence of severe AKI, not BWF, was associated with increased risk of in-hospital death (RR, 2.17 95% CI 1.01 to 4.64) adjusting for age, sex, and disease severity., Conclusions: BWF is associated with severe AKI in children hospitalized with a severe febrile illness. Increased awareness of AKI in the setting of BWF, and improved access to AKI diagnostics, is needed to reduce disease progression and in-hospital mortality in this high-risk group of children through early implementation of kidney-protective measures., (© 2022. The Author(s).)

Background: Systematic reviews of outcome measurement instruments are important tools in the evidence-based selection of these instruments. COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) has developed a comprehensive and widespread guideline to conduct systematic reviews of outcome measurement instruments, but key information is often missing in published reviews. This hinders the appraisal of the quality of outcome measurement instruments, impacts the decisions of knowledge users regarding their appropriateness, and compromises reproducibility and interpretability of the reviews' findings. To facilitate sufficient, transparent, and consistent reporting of systematic reviews of outcome measurement instruments, an extension of the PRISMA (Preferred Reporting of Items for Systematic reviews and Meta-Analyses) 2020 guideline will be developed: the PRISMA-COSMIN guideline., Methods: The PRISMA-COSMIN guideline will be developed in accordance with recommendations for reporting guideline development from the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network. First, a candidate reporting item list will be created through an environmental literature scan and expert consultations. Second, an international Delphi study will be conducted with systematic review authors, biostatisticians, epidemiologists, psychometricians/clinimetricians, reporting guideline developers, journal editors as well as patients, caregivers, and members of the public. Delphi panelists will rate candidate items for inclusion on a 5-point scale, suggest additional candidate items, and give feedback on item wording and comprehensibility. Third, the draft PRISMA-COSMIN guideline and user manual will be iteratively piloted by applying it to systematic reviews in several disease areas to assess its relevance, comprehensiveness, and comprehensibility, along with usability and user satisfaction. Fourth, a consensus meeting will be held to finalize the PRISMA-COSMIN guideline through roundtable discussions and voting. Last, a user manual will be developed and the final PRISMA-COSMIN guideline will be disseminated through publications, conferences, newsletters, and relevant websites. Additionally, relevant journals and organizations will be invited to endorse and implement PRISMA-COSMIN. Throughout the project, evaluations will take place to identify barriers and facilitators of involving patient/public partners and employing a virtual process., Discussion: The PRISMA-COSMIN guideline will ensure that the reports of systematic reviews of outcome measurement instruments are complete and informative, enhancing their reproducibility, ease of use, and uptake., (© 2022. The Author(s).)

Background: Patients receiving intermittent hemodialysis have variable times of recovery to feeling better after dialysis. QT prolongation, a precursor to clinical and subclinical cardiovascular events, may contribute to delayed recovery time. We hypothesized that abnormal electrocardiographic parameters indicating perturbations in ventricular action are associated with longer recovery times thus impacting a patient-centered quality of life., Methods: Among 242 incident in-center hemodialysis participants from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, corrected QT interval (QTc), QRST angle and heart rate variance were measured on non-dialysis days using a standard 5-min electrocardiograph recording. Left ventricular hypertrophy (LVH) was defined using the Cornell voltage product. Recovery time was ascertained during a phone interview with a standardized validated questionnaire. Associations between QTc, QRST angle, heart rate variance, and LVH and natural log-transformed recovery time were examined using linear regression adjusted for participant characteristics and electrolytes., Results: Mean age was 55 (standard deviation 13) years, 55% were male, 72% were African American. Longer QTc interval was associated with increased recovery time (per 10 ms increase in QTc, recovery time increased by 6.2%; 95% confidence interval: 0.0-10.5). QRST angle, heart rate, heart rate variability and LVH were not significantly associated with recovery time., Conclusion: Longer QTc intervals are associated with longer recovery time independent of serum electrolytes. This supports a relationship between a patient's underlying arrhythmic status and time to recovery after hemodialysis. Future studies will determine if maneuvers to reduce QTc improves recovery time and quality of life of patients on hemodialysis., (© 2022. The Author(s).)

Background: More than 90% of antibiotics are prescribed in primary care, but 50% may be unnecessary. Reducing unnecessary antibiotic overuse is needed to limit antimicrobial resistance. We conducted a pragmatic trial of a primary care provider-focused antimicrobial stewardship intervention to reduce antibiotic prescriptions in primary care., Methods: Primary care practitioners from six primary care clinics in Toronto, Ontario were assigned to intervention or control groups to evaluate the effectiveness of a multi-faceted intervention for reducing antibiotic prescriptions to adults with respiratory and urinary tract infections. The intervention included provider education, clinical decision aids, and audit and feedback of antibiotic prescribing. The primary outcome was total antibiotic prescriptions for these infections. Secondary outcomes were delayed prescriptions, prescriptions longer than 7 days, recommended antibiotic use, and outcomes for individual infections. Generalized estimating equations were used to estimate treatment effects, adjusting for clustering by clinic and baseline differences., Results: There were 1682 encounters involving 54 primary care providers from January until May 31, 2019. In intervention clinics, the odds of any antibiotic prescription was reduced 22% (adjusted Odds Ratio (OR) = 0.78; 95% Confidence Interval (CI) = 0.64.0.96). The odds that a delay in filling a prescription was recommended was increased (adjusted OR=2.29; 95% CI=1.37, 3.83), while prescription durations greater than 7 days were reduced (adjusted OR=0.24; 95% CI=0.13, 0.43). Recommended antibiotic use was similar in control (85.4%) and intervention clinics (91.8%, p=0.37)., Conclusions: A community-based, primary care provider-focused antimicrobial stewardship intervention was associated with a reduced likelihood of antibiotic prescriptions for respiratory and urinary infections, an increase in delayed prescriptions, and reduced prescription durations., Trial Registration: clinicaltrials.gov ( NCT03517215 )., (© 2021. The Author(s).)

Background: The dominant risk factor for urinary bladder cancer has been cigarette smoking, but, as smoking prevalence is decreasing in many populations, other risk factors may become uncovered. Such new risk factors could be responsible for halting the declining incidence of bladder cancer. We hypothesize that snuff use by Swedish men may increase the rate for bladder cancer, as snuff contains carcinogenic nitrosamines., Methods: We carried out an ecological study by comparing incidence trends in lung and bladder cancers between Danish, Finnish and Swedish men in order to test if the Swedish bladder cancer rate deviates from the Danish and Finnish ones. We used the NORDCAN database for cancer data from 1960 through 2016 to test the hypothesis., Results: In the three countries, the incidence of lung cancer started to decrease after a peak incidence, and this was later followed by declining incidence in bladder cancer in Denmark from 1990 to 2016 by 14.3%, in Finland by 8.3% but not in Sweden (the decline of 1.4% was not significant). The difference in trends can be partly explained by the increasing incidence in Swedish men aged 70 or more years. Sweden differs from the two other countries by low male smoking prevalence but increasing use of snuff recorded by various surveys., Conclusion: The stable bladder cancer trend for Swedish men was opposite to the declining trends in Denmark, Finland and globally. We suggest that this unusual finding may be related to the increasing use of snuff by Swedish men. Average users of snuff are exposed to at least 3 times higher levels of carcinogenic tobacco-specific nitrosamines than a smoker of one daily pack of cigarettes.

Background: Graves' disease (GD) is an autoimmune condition in which autoantibodies to the thyrotropin receptor (TSHR) cause hyperthyroidism. About 50% of GD patients also have Graves' orbitopathy (GO), an intractable disease in which expansion of the orbital contents causes diplopia, proptosis and even blindness. Murine models of GD/GO, developed in different centres, demonstrated significant variation in gut microbiota composition which correlated with TSHR-induced disease heterogeneity. To investigate whether correlation indicates causation, we modified the gut microbiota to determine whether it has a role in thyroid autoimmunity. Female BALB/c mice were treated with either vancomycin, probiotic bacteria, human fecal material transfer (hFMT) from patients with severe GO or ddH2O from birth to immunization with TSHR-A subunit or beta-galactosidase (βgal; age ~ 6 weeks). Incidence and severity of GD (TSHR autoantibodies, thyroid histology, thyroxine level) and GO (orbital fat and muscle histology), lymphocyte phenotype, cytokine profile and gut microbiota were analysed at sacrifice (~ 22 weeks)., Results: In ddH2O-TSHR mice, 84% had pathological autoantibodies, 67% elevated thyroxine, 77% hyperplastic thyroids and 70% orbital pathology. Firmicutes were increased, and Bacteroidetes reduced relative to ddH2O-βgal; CCL5 was increased. The random forest algorithm at the genus level predicted vancomycin treatment with 100% accuracy but 74% and 70% for hFMT and probiotic, respectively. Vancomycin significantly reduced gut microbiota richness and diversity compared with all other groups; the incidence and severity of both GD and GO also decreased; reduced orbital pathology correlated positively with Akkermansia spp. whilst IL-4 levels increased. Mice receiving hFMT initially inherited their GO donors' microbiota, and the severity of induced GD increased, as did the orbital brown adipose tissue volume in TSHR mice. Furthermore, genus Bacteroides, which is reduced in GD patients, was significantly increased by vancomycin but reduced in hFMT-treated mice. Probiotic treatment significantly increased CD25 + Treg cells in orbital draining lymph nodes but exacerbated induced autoimmune hyperthyroidism and GO., Conclusions: These results strongly support a role for the gut microbiota in TSHR-induced disease. Whilst changes to the gut microbiota have a profound effect on quantifiable GD endocrine and immune factors, the impact on GO cellular changes is more nuanced. The findings have translational potential for novel, improved treatments. Video abstract.

In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains.As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors.Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.

Background: Acute hypoxemic respiratory failure is one of the leading causes of intensive care unit admission and is associated with high mortality. Noninvasive oxygenation strategies such as high-flow nasal cannula, standard oxygen therapy, and noninvasive ventilation (delivered by either face mask or helmet interface) are widely available interventions applied in these patients. It remains unclear which of these interventions are more effective in decreasing rates of invasive mechanical ventilation and mortality. The primary objective of this network meta-analysis is to summarize the evidence and compare the effect of noninvasive oxygenation strategies on mortality and need for invasive mechanical ventilation in patients with acute hypoxemic respiratory failure., Methods: We will search key databases for randomized controlled trials assessing the effect of noninvasive oxygenation strategies in adult patients with acute hypoxemic respiratory failure. We will exclude studies in which the primary focus is either acute exacerbations of chronic obstructive pulmonary disease or cardiogenic pulmonary edema. The primary outcome will be all-cause mortality (longest available up to 90 days). The secondary outcomes will be receipt of invasive mechanical ventilation (longest available up to 30 days). We will assess the risk of bias for each of the outcomes using the Cochrane Risk of Bias Tool. Bayesian network meta-analyses will be conducted to obtain pooled estimates of head-to-head comparisons. We will report pairwise and network meta-analysis treatment effect estimates as risk ratios and 95% credible intervals. Subgroup analyses will be conducted examining key populations including immunocompromised hosts. Sensitivity analyses will be conducted by excluding those studies with high risk of bias and different etiologies of acute respiratory failure. We will assess certainty in effect estimates using GRADE methodology., Discussion: This study will help to guide clinical decision-making when caring for adult patients with acute hypoxemic respiratory failure and improve our understanding of the limitations of the available literature assessing noninvasive oxygenation strategies in acute hypoxemic respiratory failure., Systematic Review Registration: PROSPERO CRD42019121755.

Objective: The incidence of thyroid cancer (TC) is known to be very high in the Greater Toronto Area of Ontario, Canada. We performed a pilot survey study examining Toronto-area family physician (FP) perspectives on thyroid neoplasm evaluation (i.e. thyroid nodules [TNs] or thyroid cancer [TC]) in this region, to explore for potential factors leading to overdiagnosis., Methods: We performed a cross-sectional mail-out written survey of a random sample of 300 FPs in active practice in the Greater Toronto Area (Markham and Brampton)., Results: The overall response rate was 22.3, 95% confidence interval (CI) 18.0, 27.4% (67/300); the effective response rate was 19.9, 95% CI 15.7, 24.9% (58/291), after excluding 6 FPs that reported TN evaluation was outside their scope of practice and three FPs with an invalid mailing address. There were no missing responses to questions. The demographic characteristics were as follows: 58.6% (34/58) from Markham, 55.2% (32/58) were female, 58.6% (34/58) were in practice > 10 years, and 32.8% (19/58) affiliated with a University. All FPs reported easy access to thyroid ultrasound (TUS). About half of FPs were concerned about overdiagnosis of TC and most did not believe that there was any TC survival advantage with routine screening TUS. Although appropriate indications for TUS were endorsed by most respondents (e.g. palpable TN, incidental TN on other imaging), inappropriate recommendations were observed in a third of FPs (19/57) who recommended TUS for abnormal thyroid blood tests about half of FPs (30/56) who endorsed biopsy of sub-centimeter nodules. About half of FPs (31/58) reported that their patients sometimes request medically unnecessary TUS., Conclusion: There are likely multiple complex factors leading to potential overdiagnosis of TC in primary care, including some physicians' knowledge gaps about appropriate indications for TN investigations as well as patients' requests and expectations.

Background: Prolonged QT interval in hemodialysis patients may be associated with sudden cardiac death, however, few studies examined the longitudinal associations of modifiable factors such as serum and dialysate concentrations of calcium, potassium, and magnesium with corrected QT (QTc) prolongation in incident hemodialysis patients., Methods: In 330 in-center hemodialysis participants from the PACE study who were followed up for one year, we examined the associations of predialysis serum electrolytes (total calcium [Ca], corrected Ca [cCa], ionized Ca [iCa], potassium [K], magnesium [Mg]), dialysate (dCa and dK), and serum-to-dialysate gradient measures with QTc interval and prolongation (≥460 ms in women and ≥ 450 ms in men)., Results: At the first study visit, 47% had QTc prolongation. Lower iCa and K were associated with longer QTc interval independent of potential confounders (QTc difference = 8.55[95% CI: 2.13, 14.97] ms for iCa; QTc difference = 9.89[1.58, 18.20] ms for K). Lower iCa was also associated with a higher risk of QTc prolongation. At 1 year of follow-up, 31% had persistent QTc prolongation. In longitudinal analyses, the associations of iCa and K with QTc interval remained significant, and lower K was associated with a higher risk of QTc prolongation while the association of iCa with QTc prolongation was borderline statistically significant. Serum Mg, dCa or dK, and respective gradients were not associated with QTc interval or prolongation., Conclusion: Prolonged QTc is very common in incident hemodialysis participants and persists over follow-up. Ionized Ca and K are consistently inversely associated with QTc prolongation, which suggests closer monitoring for a low calcium or potassium level to mitigate risk.

Background: Cutaneous epithelioid angiomatous nodule (CEAN) is a very rare and relatively recently recognized vascular proliferation characterized usually by minimal cytological atypia and accompanying mitotic activity. As such, CEAN represents an important diagnostic pitfall, which could lead to significant misdiagnosis and unnecessary treatment., Methods: The clinicopathologic findings of 5 cases of CEAN were reviewed including a unique case with typical findings but also moderate cytologic atypia and brisk mitotic activity in a patient on immunosuppression., Results: The cases were in 3 women and 2 men ranging in age from 18 to 61 years with lesions in the neck (2 cases), upper arm, back and shoulder. In 4 of the cases, the patients did not have any relevant potentially contributory clinical history, and in 1 case the patient was on immunosuppressive treatment. All 5 cases were superficially located within the dermis, well-circumscribed and similarly composed of epithelioid cells displaying minimal (in 4 cases) and moderate (1 case) atypia. The mitotic count ranged from 1 to 3 per 10 high power fields (HPF) in 4 cases and up to 9 per 10 HPF in the immunosuppressed patient. Atypical mitoses were not encountered in any of the cases. Two lesions that were incompletely excised recurred, but none of the patients showed distant metastases., Conclusion: While cytologically alarming, CEAN has a characteristic microscopic appearance and if completely excised follows an indolent course.

Background: Variation in induced models of autoimmunity has been attributed to the housing environment and its effect on the gut microbiota. In Graves' disease (GD), autoantibodies to the thyrotropin receptor (TSHR) cause autoimmune hyperthyroidism. Many GD patients develop Graves' orbitopathy or ophthalmopathy (GO) characterized by orbital tissue remodeling including adipogenesis. Murine models of GD/GO would help delineate pathogenetic mechanisms, and although several have been reported, most lack reproducibility. A model comprising immunization of female BALBc mice with a TSHR expression plasmid using in vivo electroporation was reproduced in two independent laboratories. Similar orbital disease was induced in both centers, but differences were apparent (e.g., hyperthyroidism in Center 1 but not Center 2). We hypothesized a role for the gut microbiota influencing the outcome and reproducibility of induced GO., Results: We combined metataxonomics (16S rRNA gene sequencing) and traditional microbial culture of the intestinal contents from the GO murine model, to analyze the gut microbiota in the two centers. We observed significant differences in alpha and beta diversity and in the taxonomic profiles, e.g., operational taxonomic units (OTUs) from the genus Lactobacillus were more abundant in Center 2, and Bacteroides and Bifidobacterium counts were more abundant in Center 1 where we also observed a negative correlation between the OTUs of the genus Intestinimonas and TSHR autoantibodies. Traditional microbiology largely confirmed the metataxonomics data and indicated significantly higher yeast counts in Center 1 TSHR-immunized mice. We also compared the gut microbiota between immunization groups within Center 2, comprising the TSHR- or βgal control-immunized mice and naïve untreated mice. We observed a shift of the TSHR-immunized mice bacterial communities described by the beta diversity weighted Unifrac. Furthermore, we observed a significant positive correlation between the presence of Firmicutes and orbital-adipogenesis specifically in TSHR-immunized mice., Conclusions: The significant differences observed in microbiota composition from BALBc mice undergoing the same immunization protocol in comparable specific-pathogen-free (SPF) units in different centers support a role for the gut microbiota in modulating the induced response. The gut microbiota might also contribute to the heterogeneity of induced response since we report potential disease-associated microbial taxonomies and correlation with ocular disease.

Background: Collecting patient reported outcome measures (PROMs) via computer-based electronic data capture system may improve feasibility and facilitate implementation in clinical care. We report our initial experience about the acceptability of touch-screen tablet computer-based, self-administered questionnaires among patients with chronic kidney disease (CKD), including stage 5 CKD treated with renal replacement therapies (RRT) (either dialysis or transplant)., Methods: We enrolled a convenience sample of patients with stage 4 and 5 CKD (including patients on dialysis or after kidney transplant) in a single-centre, cross-sectional pilot study. Participants completed validated questionnaires programmed on an electronic data capture system (DADOS, Techna Inc., Toronto) on tablet computers. The primary objective was to evaluate the acceptability and feasibility of using tablet-based electronic data capture in patients with CKD. Descriptive statistics, Fischer's exact test and multivariable logistic regression models were used for data analysis., Results: One hundred and twenty one patients (55% male, mean age (± SD) of 58 (±14) years, 49% Caucasian) participated in the study. Ninety-two percent of the respondents indicated that the computer tablet was acceptable and 79% of the participants required no or minimal help for completing the questionnaires. Acceptance of tablets was lower among patients 70 years or older (75% vs. 95%; p = 0.011) and with little previous computer experience (81% vs. 96%; p = 0.05). Furthermore, a greater level of assistance was more frequently required by patients who were older (45% vs. 15%; p = 0.009), had lower level of education (33% vs. 14%; p = 0.027), low health literacy (79% vs. 12%; p = 0.027), and little previous experience with computers (52% vs. 10%; p = 0.027)., Conclusions: Tablet computer-based electronic data capture to administer PROMs was acceptable and feasible for most respondents and could therefore be used to systematically assess PROMs among patients with CKD. Special consideration should focus on elderly patients with little previous computer experience, since they may require more assistance with completion.

Background: Thyroid cancer has been rapidly rising in incidence in Canada; however, in contrast, lung cancer appears to be decreasing in incidence in Canadian men and stable in women. Moreover, disease-related mortality risk is generally very low in TC but high in LC. We performed a geographic spatial analysis in metropolitan Toronto, Canada to determine if there is regional variability of respective risks of thyroid cancer (TC) and lung cancer (LC), among women. Women were of particular interest for this study, given their known predilection for thyroid cancer., Methods: The postal codes of all females with TC or LC, residing in metropolitan Toronto from 2004 to 2008, were geocoded to point locations according to 2006 Canadian Census data. The data were analysed using a log-Gaussian Cox Process, where the intensity of age-adjusted cancer cases was modelled as a log-linear combination of the population at risk, explanatory variables (race, immigration, and median household income), and a residual spatially varying random effect. For each respective malignancy, statistical models were fit to make quantify the relationship between cancer incidence and explanatory variables., Results: We included 2230 women with TC and 2412 with LC. The distribution of TC and LC cases contrasted inversely among Toronto neighbourhoods with the highest TC incidence in the Northeast and the highest LC incidence in the Southeast. A higher proportion of Asian ethnicity was associated with higher regional risk of TC and lower risk of LC. A higher proportion of recent immigrants was associated with increased LC and lower TC risk, whereas median household income and proportions of African ethnicity were not significantly associated with risk of either cancer, after adjustment for other socio-demographic variables., Conclusions: We observed contrasting regional distributions of female TC and LC cases in Toronto. The differences were partly attributed to ethnic composition variability and the proportion of recent immigrants, but substantial unexplained residual variation of incidence patterns of these malignancies exists, suggesting that more individual-level research is needed to explain the regional variability of incidence of these malignancies.

Background: Germ cell neoplasia in situ (GCNIS), is preinvasive stage of testicular germ cell tumours (TGCTs). Fibrillins, which are integral components of microfibrils are suggested to be involved in cancer pathogenesis and maintenance of embryonic stem cells pluripotency. The aim of this study was to examine fibrillin-1 (FBN-1) expression in TGCTs patients., Methods: Surgical specimens from 203 patients with TGCTs were included into the translational study. FBN-1 expression was evaluated in the tumour tissue, in GCNIS and in adjacent non-neoplastic testicular tissue in all available cases. Tissue samples were processed by the tissue microarray method. FBN-1 was detected by immunohistochemistry using goat polyclonal antibody and the expression was evaluated by the multiplicative quickscore (QS)., Results: The highest FBN-1 positivity was detected in GCNIS (mean QS = 11.30), with overexpression of FBN-1 (QS >9) in the majority (77.1 %) of cases. Expression of FBN-1 in all subtypes of TGCTs was significantly lower in comparison to expression in GCNIS (all p <0.001). Seminoma had significantly higher expression compared to EC, ChC and TER (all p <0.05), but not to YST (p = 0.84). In non-neoplastic testicular tissue the FBN-1 positivity was very low (mean QS = 0.02). Sensitivity, specificity, positive and negative predictive value of FBN-1 expression for diagnosis of GCNIS were 97.1, 98.8, 98.6 and 97.7 %., Conclusions: FBN-1 is overexpressed in TGCTs and especially in GCNIS when compared to non-neoplastic testicular tissue in patients with germ cell tumors and could be involved in germ cell neoplasia in situ development.

Background: A lack of advanced healthcare information systems and validated scientific cohorts in Nicaragua makes it difficult to estimate disease prevalences and other public health statistics. Although there is concern of an "epidemic" of chronic kidney disease (CKD) in this country, statistics regarding its magnitude are derived from only a small number of non-representative studies. Budgetary constraints and the logistical problems of maintaining a study cohort make longitudinal studies difficult. The Rivas Cohort was created to measure disease burden of CKD and other public health priorities in the Department of Rivas, Nicaragua. Using primarily volunteer research students and technologic innovation including GPS, digital photography and point of care biochemical analysis, the ability to establish a longitudinal chronic disease cohort is demonstrated., Methods: Subjects were recruited from consecutive adjacent households in thirty-two randomly selected communities in the ten municipalities that comprise the Department of Rivas in southern Pacific coastal Nicaragua. The study was conducted in two phases. In the first phase, subjects were enrolled into the cohort and consented for future re-contact. In Phase II, conducted two years later, attempts were made to re-contact 400 of these subjects for additional data collection. Demographic, lifestyle, occupational, exposure and health data was collected for both phases of the study. Blood and urine testing and height, weight and blood pressure measurements were also performed. GPS coordinates of homes were recorded and maps of remote communities created., Results: Of 1397 adults living in 533 households approached for participation a total of 1242 (89 %) were enrolled in the cohort. The median age is 41 years and 43 % are male, demographics in agreement with Nicaraguan census data for the Department of Rivas. During Phase II we attempted to re-contact 400 subjects for a follow-up study of CKD. It was possible to re-contact 84 % of these participants and of those re-contacted 95 % agreed to participate in the follow-up study. Of subjects that were not successfully re-contacted the majority had either moved (32) or were not at home (22) at the time of the study team visits., Conclusion: The Rivas Cohort Study enrolled a representative sample of 1242 adults living in the Department of Rivas, Nicaragua. The high re-contact and participation rates at two years suggests that the cohort is suitable for long-term studies and presents opportunities for investigations of disease prevalence, incidence, treatment and other public health matters. GPS coordinates and maps are available for future researchers who wish to use the cohort for additional studies.

Background: Glomerular diseases are potentially fatal, requiring aggressive interventions and close monitoring. Urine is a readily-accessible body fluid enriched in molecular signatures from the kidney and therefore particularly suited for routine clinical analysis as well as development of non-invasive biomarkers for glomerular diseases., Methods: The Nephrotic Syndrome Study Network (NEPTUNE; ClinicalTrials.gov Identifier NCT01209000) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes standardized urine collections across all participating centers for the purpose of discovering non-invasive biomarkers for patients with nephrotic syndrome due to minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Here we describe the organization and methods of urine procurement and banking procedures in NEPTUNE., Results: We discuss the rationale for urine collection and storage conditions, and demonstrate the performance of three experimental analytes (neutrophil gelatinase-associated lipocalin [NGAL], retinol binding globulin, and alpha-1 microglobulin) under these conditions with and without urine preservatives (thymol, toluene, and boric acid). We also demonstrate the quality of RNA and protein collected from the urine cellular pellet and exosomes., Conclusions: The urine collection protocol in NEPTUNE allows robust detection of a wide range of proteins and RNAs from urine supernatant and pellets collected longitudinally from each patient over 5 years. Combined with the detailed clinical and histopathologic data, this provides a unique resource for exploration and validation of new or accepted markers of glomerular diseases., Trial Registration: ClinicalTrials.gov Identifier NCT01209000.

Background: Higher left ventricular mass (LV) strongly predicts cardiovascular mortality in hemodialysis patients. Although several parameters of preload and afterload have been associated with higher LV mass, whether these parameters independently predict LV mass, remains unclear., Methods: This study examined a cohort of 391 adults with incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study. The main exposures were systolic and diastolic blood pressure (BP), pulse pressure, arterial stiffness by pulse wave velocity (PWV), volume status estimated by pulmonary pressures using echocardiogram and intradialytic weight gain. The primary outcome was baseline left ventricular mass index (LVMI)., Results: Each systolic, diastolic blood, and pulse pressure measurement was significantly associated with LVMI by linear regression regardless of dialysis unit BP or non-dialysis day BP measurements. Adjusting for cardiovascular confounders, every 10 mmHg increase in systolic or diastolic BP was significantly associated with higher LVMI (SBP β = 7.26, 95 % CI: 4.30, 10.23; DBP β = 10.05, 95 % CI: 5.06, 15.04), and increased pulse pressure was also associated with higher LVMI (β = 0.71, 95 % CI: 0.29, 1.13). Intradialytic weight gain was also associated with higher LVMI but attenuated effects after adjustment (β = 3.25, 95 % CI: 0.67, 5.83). PWV and pulmonary pressures were not associated with LVMI after multivariable adjustment (β = 0.19, 95 % CI: -1.14, 1.79; and β = 0.10, 95 % CI: -0.51, 0.70, respectively). Simultaneously adjusting for all main exposures demonstrated that higher BP was independently associated with higher LVMI (SBP β = 5.64, 95 % CI: 2.78, 8.49; DBP β = 7.29, 95 % CI: 2.26, 12.31, for every 10 mmHg increase in BP)., Conclusions: Among a younger and incident hemodialysis population, higher systolic, diastolic, or pulse pressure, regardless of timing with dialysis, is most associated with higher LV mass. Future studies should consider the use of various BP measures in examining the impact of BP on LVM and cardiovascular disease. Findings from such studies could suggest that high BP should be more aggressively treated to promote LVH regression in incident hemodialysis patients.

Background: Patient decision aids (P-DAs) are used to inform patients about healthcare choices, but there is limited knowledge about their longer term effects, beyond the time period of decision-making., Methods/design: We developed a computerized P-DA that explains the choice of radioactive iodine (RAI) adjuvant treatment or no RAI, for patients with low risk papillary thyroid cancer after total thyroidectomy. The original protocol for a randomized controlled trial, comparing the use of the P-DA (with usual care) to usual care alone, has been published in Trials http://www.trialsjournal.com/content/11/1/81. We found that P-DA (with usual care) significantly improved patients' medical knowledge at the time of decision-making (primary outcome) compared to usual care alone (control). In this update, we present the protocol for an extended follow-up study (15 to 23 months post-randomization), including qualitative and quantitative methods. The patient outcomes evaluated using quantitative questionnaires include: the degree to which patients feel well-informed about their RAI treatment choice, decision satisfaction, decision regret, cancer-related worry, mood, and trust in the treating physician. The qualitative component explores the experiences of RAI treatment decision-making, treatment satisfaction, and trial participation in a representative subgroup of patients. Extended follow-up study results will be described for the entire study population, and data will be compared between the P-DA and control groups., Result and Conclusion: This mixed methods extended follow-up study will provide data on long term outcomes, relating to the use of a computerized P-DA in decision-making about adjuvant RAI treatment in early stage papillary thyroid cancer., Discussion: Our results are intended to inform future research in this area, particularly relating to long term effects of the use of P-DAs in making healthcare choices., Trial Registration: Clinicaltrials.gov identifier NCT01083550, registered 24 February 2010 and last updated 5 January 2015.

Background: Sudden cardiac death occurs commonly in the end-stage renal disease population receiving dialysis, with 25% dying of sudden cardiac death over 5 years. Despite this high risk, surprisingly few prospective studies have studied clinical- and dialysis-related risk factors for sudden cardiac death and arrhythmic precursors of sudden cardiac death in end-stage renal disease., Methods/design: We present a brief summary of the risk factors for arrhythmias and sudden cardiac death in persons with end-stage renal disease as the rationale for the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, a prospective cohort study of patients recently initiated on chronic hemodialysis, with the overall goal to understand arrhythmic and sudden cardiac death risk. Participants were screened for eligibility and excluded if they already had a pacemaker or an automatic implantable cardioverter defibrillator. We describe the study aims, design, and data collection of 574 incident hemodialysis participants from the Baltimore region in Maryland, U.S.A.. Participants were recruited from 27 hemodialysis units and underwent detailed clinical, dialysis and cardiovascular evaluation at baseline and follow-up. Cardiovascular phenotyping was conducted on nondialysis days with signal averaged electrocardiogram, echocardiogram, pulse wave velocity, ankle, brachial index, and cardiac computed tomography and angiography conducted at baseline. Participants were followed annually with study visits including electrocardiogram, pulse wave velocity, and ankle brachial index up to 4 years. A biorepository of serum, plasma, DNA, RNA, and nails were collected to study genetic and serologic factors associated with disease., Discussion: Studies of modifiable risk factors for sudden cardiac death will help set the stage for clinical trials to test therapies to prevent sudden cardiac death in this high-risk population.

Background: There is a lack of effective and affordable technologies to address health needs in the developing world. One way to address problems of innovation and affordability is to design global health technologies to follow agreed-upon standards. This Debate article argues that we can better develop standards for global health technologies if we learn lessons from other industries., Discussion: The article's Background section begins by explaining why standards are needed in global health. For example, if global health technologies can be modularized into independent interfacing parts, these parts can then interact via well-defined standards in a "plug and play" fashion. This can avoid development of mutually incompatible solutions by different organizations, speed the pace of innovation, unlock health systems from single providers and approaches, and lower barriers to entry. The Background then gives a brief primer on standards and discusses incentives for health standards. The article's Discussion section begins with brief relevant cases of standards development from other industries, including electricity, container shipping, CD standards, Universal Serial Bus (USB), and the Internet. It then explores lessons from these and other industries that suggest how to develop standards for global health technologies. The remainder of the Discussion considers intellectual property and regulatory issues and standards-based global health business models, and ends with a checklist of considerations for health standards development leaders. (The associated Additional file discusses observations from standards development for cell phones and semiconductors, as well as challenges in the standards development process itself.) Throughout the article, point-of-care diagnostics are used as an illustrative example. An initiative is already underway to explore standardized diagnostics platforms., Summary: This Debate article aims to convince the reader that standards can benefit global health technologies if we learn lessons from other industries. The article draws from historical examples and the authors' experiences to suggest principles, challenges, and opportunities in developing these standards. If implemented well, standardized platforms can lower barriers to entry, improve affordability, and create a vibrant ecosystem of innovative new global health technologies.

Background: Although the World Health Organization had recommended that every child be vaccinated for Hepatitis B by the early 1980s, large multinational pharmaceutical companies held monopolies on the recombinant Hepatitis B vaccine. At a price as high as USD$23 a dose, most Indians families could not afford vaccination. Shantha Biotechnics, a pioneering Indian biotechnology company founded in 1993, saw an unmet need domestically, and developed novel processes for manufacturing Hepatitis B vaccine to reduce prices to less than $1/dose. Further expansion enabled low-cost mass vaccination globally through organizations such as UNICEF. In 2009, Shantha sold over 120 million doses of vaccines. The company was recently acquired by Sanofi-Aventis at a valuation of USD$784 million., Methods: The case study and grounded research method was used to illustrate how the globalization of healthcare R&D is enabling private sector companies such as Shantha to address access to essential medicines. Sources including interviews, literature analysis, and on-site observations were combined to conduct a robust examination of Shantha's evolution as a major provider of vaccines for global health indications., Results: Shantha's ability to become a significant global vaccine manufacturer and achieve international valuation and market success appears to have been made possible by focusing first on the local health needs of India. How Shantha achieved this balance can be understood in terms of a framework of four guiding principles. First, Shantha identified a therapeutic area (Hepatitis B) in which cost efficiencies could be achieved for reaching the poor. Second, Shantha persistently sought investments and partnerships from non-traditional and international sources including the Foreign Ministry of Oman and Pfizer. Third, Shantha focused on innovation and quality - investing in innovation from the outset yielded the crucial process innovation that allowed Shantha to make an affordable vaccine. Fourth, Shantha constructed its own cGMP facility, which established credibility for vaccine prequalification by the World Health Organization and generated interest from large pharmaceutical companies in its contract research services. These two sources of revenue allowed Shantha to continue to invest in health innovation relevant to the developing world., Conclusions: The Shantha case study underscores the important role the private sector can play in global health and access to medicines. Home-grown companies in the developing world are becoming a source of low-cost, locally relevant healthcare R&D for therapeutics such as vaccines. Such companies may be compelled by market forces to focus on products relevant to diseases endemic in their country. Sanofi-Aventis' acquisition of Shantha reveals that even large pharmaceutical companies based in the developed world have recognized the importance of meeting the health needs of the developing world. Collectively, these processes suggest an ability to tap into private sector investments for global health innovation, and illustrate the globalization of healthcare R&D to the developing world.

Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL)(-/-) mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4(+) and CD8(+) T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.

Background: Biopiracy - the use of a people's long-established medical knowledge without acknowledgement or compensation - has been a disturbing historical reality and exacerbates the global rich-poor divide. Bioprospecting, however, describes the commercialization of indigenous medicines in a manner acceptable to the local populace. Challenges facing bioprospectors seeking to develop traditional medicines in a quality-controlled manner include a lack of skilled labor and high-tech infrastructure, adapting Northern R&D protocols to Southern settings, keeping products affordable for the local population, and managing the threat of biopiracy. The Malagasy Institute of Applied Research (IMRA) has employed bioprospecting to develop new health treatments for conditions such as diabetes and burns. Because of its integration of Western science and Malagasy cultural traditions, IMRA may provide a useful example for African and other organizations interested in bioprospecting., Discussion: IMRA's approach to drug development and commercialization was adapted from the outset to Malagasy culture and Southern economic landscapes. It achieved a balance between employing Northern R&D practices and following local cultural norms through four guiding principles. First, IMRA's researchers understood and respected local practices, and sought to use rather than resist them. Second, IMRA engaged the local community early in the drug development process, and ensured that local people had a stake in its success. Third, IMRA actively collaborated with local and international partners to increase its credibility and research capacity. Fourth, IMRA obtained foreign research funds targeting the "diseases of civilization" to cross-fund the development of drugs for conditions that affect the Malagasy population. These principles are illustrated in the development of IMRA products like Madeglucyl, a treatment for diabetes management that was developed from a traditional remedy., Summary: By combining local and international research interests, IMRA has been able to keep its treatments affordable for the Malagasy population. Our analysis of IMRA's history, strategy, and challenges suggests that other developing world institutions seeking to use bioprospecting to address issues of local access to medicines would be well-advised to treat traditional medical knowledge with respect and humility, share its benefits with the local community, and pursue strategic partnerships.

Background: A traditional pathway for developing new health products begins with public research institutes generating new knowledge, and ends with the private sector translating this knowledge into new ventures. But while public research institutes are key drivers of basic research in sub-Saharan Africa, the private sector is inadequately prepared to commercialize ideas that emerge from these institutes, resulting in these institutes taking on the role of product development themselves to alleviate the local disease burden. In this article, the case study method is used to analyze the experience of one such public research institute: the Kenya Medical Research Institute (KEMRI)., Discussion: Our analysis indicates that KEMRI's product development efforts began modestly, and a manufacturing facility was constructed with a strategy for the facility's product output which was not very successful. The intended products, HIV and Hepatitis B diagnostic kits, had a short product life cycle, and an abrupt change in regulatory requirements left KEMRI with an inactive facility. These problems were the result of poor innovation management capacity, variability in domestic markets, lack of capital to scale up technologies, and an institutional culture that lacked innovation as a priority.However, KEMRI appears to have adapted by diversifying its product line to mitigate risk and ensure continued use of its manufacturing facility. It adopted an open innovation business model which linked it with investors, research partnerships, licensing opportunities, and revenue from contract manufacturing. Other activities that KEMRI has put in place over several years to enhance product development include the establishment of a marketing division, development of an institutional IP policy, and training of its scientists on innovation management., Summary: KEMRI faced many challenges in its attempt at health product development, including shifting markets, lack of infrastructure, inadequate financing, and weak human capital with respect to innovation. However, it overcame them through diversification, partnerships and changes in culture. The findings could have implications for other research institutes in Sub-Saharan Africa seeking to develop health products. Such institutes must analyze potential demand and uptake, yet be prepared to face the unexpected and develop appropriate risk-mitigating strategies.

Background: Science, technology and innovation have long played a role in Ghana's vision for development, including in improving its health outcomes. However, so far little research has been conducted on Ghana's capacity for health innovation to address local diseases. This research aims to fill that gap, mapping out the key actors involved, highlighting examples of indigenous innovation, setting out the challenges ahead and outlining recommendations for strengthening Ghana's health innovation system., Methods: Case study research methodology was used. Data were collected through reviews of academic literature and policy documents and through open-ended, face-to-face interviews with 48 people from across the science-based health innovation system. Data was collected over three visits to Ghana from February 2007 to August 2008, and stakeholders engaged subsequently., Results: Ghana has strengths which could underpin science-based health innovation in the future, including health and biosciences research institutions with strong foreign linkages and donor support; a relatively strong regulatory system which is building capacity in other West African countries; the beginnings of new funding forms such as venture capital; and the return of professionals from the diaspora, bringing expertise and contacts. Some health products and services are already being developed in Ghana by individual entrepreneurs, which are innovative in the sense of being new to the country and, in some cases, the continent. They include essential medicines, raw pharmaceutical materials, new formulations for pediatric use and plant medicines at various stages of development., Conclusions: While Ghana has many institutions concerned with health research and its commercialization, their ability to work together to address clear health goals is low. If Ghana is to capitalize on its assets, including political and macroeconomic stability which underpin investment in health enterprises, it needs to improve the health innovation environment through increasing support for its small firms; coordinating policies; and beginning a dialogue with donors on how health research can create locally-owned knowledge and be more demand-driven. Mobilizing stakeholders around health product development areas, such as traditional medicines and diagnostics, would help to create trust between groups and build a stronger health innovation system.

Background: Field trials have demonstrated the efficacy of insecticide-treated nets, and the WHO has recently endorsed a shift toward Long-Lasting Insecticide Treated nets (LLINs) due to factors such as reduced distribution costs. However, the need for LLINs poses several challenges. Is it possible to manufacture LLINs in large quantities in the African continent, where malaria is most endemic? When production is located in low-income countries, what role is played by local funding and employment, scaling up manufacturing, and partnerships? What factors influence availability and pricing?, Discussion: A case study of A to Z Textiles was undertaken to answer the question of how large-scale production of LLINs can occur in a low income setting. One of the largest sources of bed nets for Africa, A to Z Textiles is Africa-based, and its Tanzanian operations have a production capacity of 30 million LLINs per year, along with full WHO recommendation for its nets. Our analysis is based on semi-structured interviews with key informants familiar with A to Z, site visits in Tanzania, and literature reviews.This paper discusses the history and current status of A to Z Textiles, identifies the factors that led to its success, and suggests policy considerations that could support similar initiatives in the future. Local funding, scaling up manufacturing, technology transfer, and partnerships all played important roles in A to Z's ascent, as did perceived benefits of local employment and capacity-building. Regulatory issues and procurement rules acted as barriers. A to Z cost-effectively manufactures high-quality LLINs where malaria is most endemic., Summary: With a production capacity of 30 million LLINs per year, and full WHOPES (WHO Pesticide Evaluation Scheme) certification, A to Z Textiles demonstrates how key health goods can be successfully produced in the low-income countries that use them. Its example may be instructive and of high interest to readers in the malaria community, especially in developing countries, and to those who wish to support or partner with efforts by developing countries to build their health innovation capacity.

Background: This paper describes and analyses Rwanda's science-based health product 'innovation system', highlighting examples of indigenous innovation and good practice. We use an innovation systems framework, which takes into account the wide variety of stakeholders and knowledge flows contributing to the innovation process. The study takes into account the destruction of the country's scientific infrastructure and human capital that occurred during the 1994 genocide, and describes government policy, research institutes and universities, the private sector, and NGOs that are involved in health product innovation in Rwanda., Methods: Case study research methodology was used. Data were collected through reviews of academic literature and policy documents and through open-ended, face-to-face interviews with 38 people from across the science-based health innovation system. Data was collected over two visits to Rwanda between November - December 2007 and in May 2008. A workshop was held in Kigali on May 23rd and May 24th 2009 to validate the findings. A business plan was then developed to operationalize the findings., Results and Discussion: The results of the study show that Rwanda has strong government will to support health innovation both through its political leadership and through government policy documents. However, it has a very weak scientific base as most of its scientific infrastructure as well as human capital were destroyed during the 1994 genocide. The regulatory agency is weak and its nascent private sector is ill-equipped to drive health innovation. In addition, there are no linkages between the various actors in the country's health innovation system i.e between research institutions, universities, the private sector, and government bureaucrats., Conclusions: Despite the fact that the 1994 genocide destroyed most of the scientific infrastructure and human capital, the country has made remarkable progress towards developing its health innovation system, mainly due to political goodwill. The areas of greatest potential for Rwanda are in traditional plant technologies. However, there is need for investments in domestic skill development as well as infrastructure that will enhance innovation. Of foremost importance is the establishment of a platform to link the various actors in the health innovation system.

Background: Tanzania is East Africa's largest country. Although it is socially diverse, it has experienced general political stability since independence in 1964. Despite gradual economic development and Tanzania's status as one of the biggest recipients of aid in Africa, health status remains poor. This paper explores Tanzania's science-based health innovation system, and highlights areas which can be strengthened., Methods: Qualitative case study research methodology was used. Data were collected through reviews of academic literature and policy documents, and through open-ended, face-to-face interviews with 52 people from across the science-based health innovation system over two visits to Tanzania from July to October 2007., Results and Discussion: Tanzania has a rich but complex S&T governance landscape, with the public sector driving the innovation agenda through a series of different bodies which are not well-coordinated. It has some of the leading health research on the continent at the University of Dar es Salaam, Muhimbili University of Health and Applied Sciences, the National Institute for Medical Research and the Ifakara Medical Institute, with strong donor support. Tanzania has found developing an entrepreneurial culture difficult; nevertheless projects such as the clusters initiative at the University of Dar es Salaam are encouraging low-tech innovation and overcoming knowledge-sharing barriers. In the private sector, one generics company has developed a South-South collaboration to enable technology transfer and hence the local production of anti-retrovirals. Local textile company A to Z Textiles is now manufacturing 30 million insecticide impregnated bednets a year., Conclusions: To have a coherent vision for innovation, Tanzania may wish to address some key issues: coordination across stakeholders involved with health research, increasing graduates in health-related disciplines, and building capabilities in biological testing, preclinical testing, formulation and standardization, and related areas important to moving from basic research to applications. The private sector can be encouraged to innovate through improved access to financing, and incentives for R&D. The diaspora community represents an untapped source for partnerships and access to other developing world markets and technology. The government may wish to set up mechanisms to encourage south-south collaborations, and to bring the public and private sector together around specific projects to help realize the country's innovation potential.

Background: Incubators are organizations that support the growth of new and typically technology-based enterprises, by providing business support services that bring together human and financial capital. Although the traditional role of incubators has been for economic development, they may also be a useful policy lever to tackle global health, by fostering the development and delivery of local health innovation.Given its high disease burden, life sciences incubators hold particular potential for Africa. As the most industrially advanced African nation, South Africa serves as a litmus test for identifying effective incubator policies. The case study method was used to illustrate how one such publicly funded incubator founded in 2002, Acorn Technologies, helped to catalyze local health product innovation., Discussion: Acorn helped to support twelve biomedical device firms. One of them, Real World Diagnostics, was founded by a trainee from Acorn's innovative internship program (Hellfire). It developed rapid strip diagnostic tests for locally prevalent diseases including schistosomiasis and HIV, and reported $2 million (USD) in revenue in 2009.Acorn achieved this success by operating as a non-profit virtual incubator with little physical infrastructure. Employing a virtual model in combination with stringent selection criteria of capital efficiency for clients proved to be effective in reducing its own fixed costs. Acorn focused on entrepreneurship training and networking, both critical at an early stage in an environment dominated by multinational biomedical device companies.Acorn and its clients learned that employing a cross-subsidy business model allowed one to generate royalty revenue through imports to subsidize R&D for local diseases. However, funding constraints and government expectations for rapid self-sustainability forced Acorn to merge with its sister biotechnology incubator in 2009., Summary: A key to Acorn's achievements was identifying entrepreneurs with technologies with health and economic impact, and providing them with flexible support from an early stage. A virtual organizational model helped Acorn to focus on supporting entrepreneurs. Governments and funders may wish to consider incubation strategies that draw from these good practices. With the right policies and business models, incubators have the potential to generate both health and economic benefits for Africa.

Background: Since 2000, R&D financing for global health has increased significantly, with innovative proposals for further increases. However, although venture capital (VC) funding has fostered life sciences businesses across the developed world, its application in the developing world and particularly in Africa is relatively new. Is VC feasible in the African context, to foster the development and application of local health innovation?As the most industrially advanced African nation, South Africa serves as a test case for life sciences venture funding. This paper analyzes Bioventures, the first VC company focused on life sciences investment in sub-Saharan Africa. The case study method was used to analyze the formation, operation, and investment support of Bioventures, and to suggest lessons for future health venture funds in Africa that aim to develop health-oriented innovations., Discussion: The modest financial success of Bioventures in challenging circumstances has demonstrated a proof of concept that life sciences VC can work in the region. Beyond providing funds, support given to investees included board participation, contacts, and strategic services. Bioventures had to be proactive in finding and supporting good health R&D.Due to the fund's small size, overhead and management expenses were tightly constrained. Bioventures was at times unable to make follow-on investments, being forced instead to give up equity to raise additional capital, and to sell health investments earlier than might have been optimal. With the benefit of hindsight, the CFO of Bioventures felt that partnering with a larger fund might benefit similar future funds. Being better linked to market intelligence and other entrepreneurial investors was also seen as an unmet need., Summary: BioVentures has learned lessons about how the traditional VC model might evolve to tackle health challenges facing Africa, including how to raise funds and educate investors; how to select, value, and support investments; and how to understand the balance between financial and social returns. The experience of the fund suggests that future health funds targeting ailments of the poor might require investors that accept health benefits as part of their overall "return." Learning from Bioventures may help develop health innovation funding for sub-Saharan African that has combined health, financial, and economic development impacts.

Background: Uganda has a long history of health research, but still faces critical health problems. It has made a number of recent moves towards building science and technology capacity which could have an impact on local health, if innovation can be fostered and harnessed., Methods: Qualitative case study research methodology was used. Data were collected through reviews of academic literature and policy documents and through open-ended, face-to-face interviews with 30 people from across the science-based health innovation system, including government officials, researchers in research institutes and universities, entrepreneurs, international donors, and non-governmental organization representatives., Results: Uganda has a range of institutions influencing science-based health innovation, with varying degrees of success. However, the country still lacks a coherent mechanism for effectively coordinating STI policy among all the stakeholders. Classified as a least developed country, Uganda has opted for exemptions from the TRIPS intellectual property protection regime that include permitting parallel importation and providing for compulsory licenses for pharmaceuticals. Uganda is unique in Africa in taking part in the Millennium Science Initiative (MSI), an ambitious though early-stage $30m project, funded jointly by the World Bank and Government of Uganda, to build science capacity and encourage entrepreneurship through funding industry-research collaboration. Two universities - Makerere and Mbarara - stand out in terms of health research, though as yet technology development and commercialization is weak. Uganda has several incubators which are producing low-tech products, and is beginning to move into higher-tech ones like diagnostics. Its pharmaceutical industry has started to create partnerships which encourage innovation., Conclusions: Science-based health product innovation is in its early stages in Uganda, as are policies for guiding its development. Nevertheless, there is political will for the development of STI in Uganda, demonstrated through personal initiatives of the President and the government's willingness to invest heavily for the long term in support of STI through the Millennium Science Initiative. Activities to support technology transfer and private-public collaboration have been put in motion; these need to be monitored, coordinated, and learned from. In the private sector, there are examples of incremental innovation to address neglected diseases driven by entrepreneurial individuals and South-South collaboration. Lessons can be learned from their experience that will help support Ugandan health innovation.

In recent years emerging markets such as India, China, and Brazil have developed appropriate business models and lower-cost technological innovations to address health challenges locally and internationally. But it is not well understood what capabilities African countries, with their high disease burden, have in science-based health innovation.This gap in knowledge is addressed by this series in BMC International Health and Human Rights. The series presents the results of extensive on-the-ground research in the form of four country case studies of health and biotechnology innovation, six studies of institutions within Africa involved in health product development, and one study of health venture funds in Africa. To the best of our knowledge it is the first extensive collection of empirical work on African science-based health innovation.The four country cases are Ghana, Rwanda, Tanzania and Uganda. The six case studies of institutions are A to Z Textiles (Tanzania), Acorn Technologies (South Africa), Bioventures venture capital fund (South Africa), the Malagasy Institute of Applied Research (IMRA; Madagascar), the Kenyan Medical Research Institute (KEMRI; Kenya), and Niprisan's development by Nigeria's National Institute for Pharmaceutical Research and Development and Xechem (Nigeria).All of the examples highlight pioneering attempts to build technological capacity, create economic opportunities, and retain talent on a continent significantly affected by brain drain. They point to the practical challenges for innovators on the ground, and suggest potentially helpful policies, funding streams, and other support systems.For African nations, health innovation represents an opportunity to increase domestic capacity to solve health challenges; for international funders, it is an opportunity to move beyond foreign aid and dependency. The shared goal is creating self-sustaining innovation that has both health and development impacts. While this is a long-term strategy, this series shows the potential of African-led innovation, and indicates how it might balance realism against opportunity. There is ample scope to learn lessons more systematically from cases like those we discuss; to link entrepreneurs, scientists, funders, and policy-makers into a network to share opportunities and challenges; and ultimately to better support and stimulate African-led health innovation.

Background: Developing novel drugs from traditional medicinal knowledge can serve as a means to improve public health. Yet countries in sub-Saharan Africa face barriers in translating traditional medicinal knowledge into commercially viable health products. Barriers in moving along the road towards making a new drug available include insufficient manufacturing capacity; knowledge sharing between scientists and medical healers; regulatory hurdles; quality control issues; pricing and distribution; and lack of financing. The case study method was used to illustrate efforts to overcome these barriers during the development in Nigeria of Niprisan - a novel drug for the treatment of sickle cell anemia, a chronic blood disorder with few effective therapies., Discussion: Building on the knowledge of a traditional medicine practitioner, Nigeria's National Institute for Pharmaceutical Research and Development (NIPRD) developed the traditional herbal medicine Niprisan. The commercialization of Niprisan reached a number of commercial milestones, including regulatory approval in Nigeria; securing US-based commercial partner XeChem; demonstrating clinical efficacy and safety; being awarded orphan drug status by the US Food and Drug Administration; and striking important relationships with domestic and international groups. Despite these successes, however, XeChem did not achieve mainstream success for Niprisan in Nigeria or in the United States. A number of reasons, including inconsistent funding and manufacturing and management challenges, have been put forth to explain Niprisan's commercial demise. As of this writing, NIPRD is considering options for another commercial partner to take the drug forward., Summary: Evidence from the Niprisan experience suggests that establishing benefit-sharing agreements, fostering partnerships with established research institutions, improving standardization and quality control, ensuring financial and managerial due diligence, and recruiting entrepreneurial leaders capable of holding dual scientific and business responsibilities should be incorporated into future drug development initiatives based on traditional medicines. Country-level supporting policies and conditions are also important. With more experience and support, and an improved environment for innovation, developing new drugs from traditional medicines may be an attractive approach to addressing diseases in sub-Saharan Africa and other regions.

Background: While venture funding has been applied to biotechnology and health in high-income countries, it is still nascent in these fields in developing countries, and particularly in Africa. Yet the need for implementing innovative solutions to health challenges is greatest in Africa, with its enormous burden of communicable disease. Issues such as risk, investment opportunities, return on investment requirements, and quantifying health impact are critical in assessing venture capital's potential for supporting health innovation. This paper uses lessons learned from five venture capital firms from Kenya, South Africa, China, India, and the US to suggest design principles for African health venture funds., Discussion: The case study method was used to explore relevant funds, and lessons for the African context. The health venture funds in this study included publicly-owned organizations, corporations, social enterprises, and subsidiaries of foreign venture firms. The size and type of investments varied widely. The primary investor in four funds was the International Finance Corporation. Three of the funds aimed primarily for financial returns, one aimed primarily for social and health returns, and one had mixed aims. Lessons learned include the importance of measuring and supporting both social and financial returns; the need to engage both upstream capital such as government risk-funding and downstream capital from the private sector; and the existence of many challenges including difficulty of raising capital, low human resource capacity, regulatory barriers, and risky business environments. Based on these lessons, design principles for appropriate venture funding are suggested., Summary: Based on the cases studied and relevant experiences elsewhere, there is a case for venture funding as one support mechanism for science-based African health innovation, with opportunities for risk-tolerant investors to make financial as well as social returns. Such funds should be structured to overcome the challenges identified, be sustainable in the long run, attract for-profit private sector funds, and have measurable and significant health impact. If this is done, the proposed venture approach may have complementary benefits to existing initiatives and encourage local scientific and economic development while tapping new sources of funding.

Background: Patients with early stage papillary thyroid carcinoma (PTC), are faced with the decision to either to accept or reject adjuvant radioactive iodine (RAI) treatment after thryroidectomy. This decision is often difficult because of conflicting reports of RAI treatment benefit and medical evidence uncertainty due to the lack of long-term randomized controlled trials., Methods: We report the protocol for a parallel, 2-arm, randomized trial comparing an intervention group exposed to a computerized decision aid (DA) relative to a control group receiving usual care. The DA explains the options of adjuvant radioactive iodine or no adjuvant radioactive iodine, as well as associated potential benefits, risks, and follow-up implications. Potentially eligible adult PTC patient participants will include: English-speaking individuals who have had recent thyroidectomy, and whose primary tumor was 1 to 4 cm in diameter, with no known metastases to lymph nodes or distant sites, with no other worrisome features, and who have not received RAI treatment for thyroid cancer. We will measure the effect of the DA on the following patient outcomes: a) knowledge about PTC and RAI treatment, b) decisional conflict, c) decisional regret, d) client satisfaction with information received about RAI treatment, and e) the final decision to accept or reject adjuvant RAI treatment and rationale., Discussion: This trial will provide evidence of feasibility and efficacy of the use of a computerized DA in explaining complex issues relating to decision making about adjuvant RAI treatment in early stage PTC., Trial Registration: Clinical Trials.gov Identifier: NCT01083550.

Background: Many articles have been written on conflicts of interests (COIs) in fields such as medicine, business, politics, public service and education. With the growing abundance of Public Private Partnerships (PPPs), often involving complex relationships among the partners, it is important to understand how COIs can be mitigated and managed in PPPs., Discussion: We wanted to study PPPs, particularly in the areas of global health and agriculture, but discovered no single source of information available to identify and compare various approaches for avoiding and managing COIs in PPPs. This is a significant gap, especially for those wishing to study, compare and strengthen existing COI policies related to PPPs. In order to bridge this gap, we reviewed how PPPs currently address COIs and highlight what might be considered good practice in developing COI policies. We reviewed the online COI policies of 10 PPPs in global health and agriculture, and interviewed two global health PPP chief executives., Summary: Based on our review of policies and interviews, we conclude that there exists a range of good practices including attention to accountability and governance, acknowledgement and disclosure, abstention and withdrawal, reporting and transparency, and independent monitoring. There appears to be a need for PPPs to interact closely and learn from each other on these parameters and to also place more emphasis on independent external monitoring of COIs as a means of strengthening their major social objectives on which their activities are largely predicated. We also recommend the establishment of a web based database, which would serve as a forum to discuss COI issues and how they can be resolved.

Background: The defining event in the area of infant feeding is the aggressive marketing of infant formula in the developing world by transnational companies in the 1970s. This practice shattered the trust of the global health community in the private sector, culminated in a global boycott of Nestle products and has extended to distrust of all commercial efforts to improve infant and young child nutrition. The lack of trust is a key barrier along the critical path to optimal infant and young child nutrition in the developing world., Discussion: To begin to bridge this gap in trust, we developed a set of shared principles based on the following ideals: Integrity; Solidarity; Justice; Equality; Partnership, cooperation, coordination, and communication; Responsible Activity; Sustainability; Transparency; Private enterprise and scale-up; and Fair trading and consumer choice. We hope these principles can serve as a platform on which various parties in the in the infant and young child nutrition arena, can begin a process of authentic trust-building that will ultimately result in coordinated efforts amongst parties., Summary: A set of shared principles of ethics for infant and young child nutrition in the developing world could catalyze the scale-up of low cost, high quality, complementary foods for infants and young children, and eventually contribute to the eradication of infant and child malnutrition in the developing world.

Background: In recent years, the field of vaccines for diseases such as Human Immunodeficiency Virus (HIV) which take a heavy toll in developing countries has faced major failures. This has led to a call for more basic science research, and development as well as evaluation of new vaccine candidates. Human-animal chimeras, developed with a 'humanized' immune system could be useful to study infectious diseases, including many neglected diseases. These would also serve as an important tool for the efficient testing of new vaccine candidates to streamline promising candidates for further trials in humans. However, developing human-animal chimeras has proved to be controversial., Discussion: Development of human-animal chimeras for vaccine development has been slowed down because of opposition by some philosophers, ethicists and policy makers in the west-they question the moral status of such animals, and also express discomfort about transgression of species barriers. Such opposition often uses a contemporary western world view as a reference point. Human-animal chimeras are often being created for diseases which cause significantly higher morbidity and mortality in the developing world as compared to the developed world. We argue in our commentary that given this high disease burden, we should look at socio-cultural perspectives on human-animal chimera like beings in the developing world. On examination, it's clear that such beings have been part of mythology and cultural descriptions in many countries in the developing world., Summary: To ensure that important research on diseases afflicting millions like malaria, HIV, Hepatitis-C and dengue continues to progress, we recommend supporting human-animal chimera research for vaccine development in developing countries (especially China and India which have growing technical expertise in the area). The negative perceptions in some parts of the west about human-animal chimeras can be used as an opportunity for nurturing important vaccine development research in the developing world.

Background: Experience with public engagement activities regarding the risks and benefits of science and technology (S&T) is growing, especially in the industrialized world. However, public engagement in the developing world regarding S&T risks and benefits to explore health issues has not been widely explored., Methods: This paper gives an overview about public engagement and related concepts, with a particular focus on challenges and benefits in the developing world. We then describe an Internet-based platform, which seeks to both inform and engage youth and the broader public on global water issues and their health impacts. Finally, we outline a possible course for future action to scale up this and similar online public engagement platforms., Results: The benefits of public engagement include creating an informed citizenry, generating new ideas from the public, increasing the chances of research being adopted, increasing public trust, and answering ethical research questions. Public engagement also fosters global communication, enables shared experiences and methodology, standardizes strategy, and generates global viewpoints. This is especially pertinent to the developing world, as it encourages previously marginalized populations to participate on a global stage. One of the core issues at stake in public engagement is global governance of science and technology. Also, beyond benefiting society at large, public engagement in science offers benefits to the scientific enterprise itself., Conclusion: Successful public engagement with developing world stakeholders will be a critical part of implementing new services and technologies. Interactive engagement platforms, such as the Internet, have the potential to unite people globally around relevant health issues.