Vaccine safety surveillance in Kenya using GAIA standards: A feasibility assessment of existing national and subnational research and program systems.

BACKGROUND: Active surveillance systems for monitoring vaccine safety among pregnant women address some of the limitations of a current passive surveillance approach utilized in low- and middle-income countries (LMIC). However, few active surveillance systems in LMIC exist. Our study assessed the feasibility of utilizing three existing data collection systems in Kenya for active surveillance of maternal immunization and to assess the applicability of Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) case definitions that were initially developed for clinical trials within these systems. METHODS: We assessed applicability of GAIA case definition for maternal Tetanus Toxoid exposure, stillbirth, low birth weight, small for gestational age, Neonatal Invasive Blood Stream Infection (NIBSI), prematurity and neonatal death in two routine web-based health information systems (Kenya EMR and DHIS-2), and a web-based population-based pregnancy research platform (ANCOV1) in Kenya. RESULTS: All three HIS were capable of reporting selected outcomes to varying degrees of GAIA certainty. The ANCOV platform was the most robust in collecting and collating clinical data for effective maternal pharmacovigilance. The utilization of facility- and district-aggregated data limits the usefulness of DHIS-2 in pharmacovigilance as currently operationalized. While the Kenya EMR contained individual level data and meets the key considerations for effective pharmacovigilance, it was used primarily for HIV care and treatment records in a small proportion of health facilities and would require additional resources to expand to all antenatal care facilities and to link maternal and infant records. DISCUSSION: Population-based research studies may offer a responsive short-term option for implementing maternal vaccine pharmacovigilance in LMICs. However, the foundation exists for long-term capacity building within the national health electronic data systems to provide this critical service as well as ensure participation of the country in international studies on maternal vaccine safety.

A risk assessment model for transfusion transmission of dengue.

Dengue virus (DENV) is a disease-causing agent normally transmitted from person to person through the bite of an infected mosquito. In addition to mosquito-borne cases of dengue, there are instances of transmission of dengue after receipt of blood products or donor organs or tissue. To improve blood safety, we developed a quantitative risk assessment model to estimate the dengue risk of transmission to blood transfusion recipients from preclinical and subclinical blood donors. We derived predictive coefficients from model simulations for predicting the risk outcomes such as monthly infectious blood units and transfusion-transmitted DENV cases based on the rate of reported clinical cases. The model was validated with a previous study where donor blood samples from the 2012 dengue transmission season in Rio de Janeiro, Brazil were tested for DENV RNA by a transcription-mediated amplification (TMA) assay. In that study, about 69·4% of donations were tested by the TMA assay and 78 samples were found positive, indicating that 112 DENV RNA-positive donations would have been detected if testing screening had been performed on all donations. Our model estimated a mean of 93 (2.5-97.5th%ile: 47-186) infected units among the donations, which was consistent with the reported numbers.

A modified dose-response model that describes the relationship between haemagglutination inhibition titre and protection against influenza infection.

AIMS: Develop a model for quantifying the risk of an adverse human response to influenza virus infection as a function of exposure dose and pre-exposure antibody titre level. METHODS AND RESULTS: We evaluated the relationship between haemagglutination inhibition (HI) titre (as a measure of specific antibody response) and protection against influenza infection and modelled this relationship by incorporating HI titre as a variable into dose-response models. Using a maximum likelihood estimation approach, the resulting model was capable of providing statistically acceptable fits to most available data. CONCLUSIONS: The incorporated HI titre dependency in the model quantifies the protective effect of antibody titre. The modelling can be used to predict the protection effectiveness associated with elevated HI titre levels post vaccination to different levels of exposures. SIGNIFICANCE AND IMPACT OF THE STUDY: The study incorporates HI titre level as a variable into a dose-response model for influenza infection. The approaches developed in this study could be used to evaluate other factors associated with the predictability of HI titre or other surrogate endpoints for influenza vaccines.

Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model.

An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia.

Modeling complete removal of risk assessment questions in the USA predicts the risk of HIV exposure in blood recipients could increase despite the use of nucleic acid testing.

BACKGROUND AND OBJECTIVES: The safety of the blood supply in a number of countries is achieved by interventions that include behaviour-based time-limited or indefinite deferrals and screening of donated units for transfusion-transmitted infections. The relatively high sensitivity of nucleic acid testing (NAT) used in blood donor screening has raised the question of whether such time-based deferrals can be eliminated in favour of individual risk assessment. MATERIALS AND METHODS: Data on the annual number of incident human immunodeficiency virus (HIV) infections associated with various behaviours and on the performance characteristics of NAT applied to donor screening were used to model the number of potentially infected units that might escape detection in the worst-case scenario in which individual risk assessment was implemented, but was not effective as a screening tool, and donors did not otherwise self-select for lower risk. RESULTS: In the absence of effective individual risk-based screening or donor self-selection, the model predicts that in the United States, an additional 39 (95% CI 35-43) HIV-infected units would escape detection by nucleic acid testing, potentially capable of exposing approximately 68 (95% CI 61-75) individuals to the risk of HIV infection through the administration of prepared blood components. CONCLUSION: Despite some inherent uncertainty, the worst-case scenario of completely ineffective individual risk assessment, absence of donor self-selection and increased reliance on NAT for blood screening is estimated to be associated with an approximately fourfold increase in the risk of HIV exposure through transfusion in the United States.

The FDA's sentinel initiative--A comprehensive approach to medical product surveillance.

In May 2008, the Department of Health and Human Services announced the launch of the Sentinel Initiative by the US Food and Drug Administration (FDA) to create the Sentinel System, a national electronic system for medical product safety surveillance. This system complements existing FDA surveillance capabilities that track adverse events reported after the use of FDA regulated products by allowing the FDA to proactively assess the safety of these products.

Clotting factor product administration and same-day occurrence of thrombotic events, as recorded in a large healthcare database during 2008-2013.

BACKGROUND: Thrombotic events (TEs) are serious adverse events that can occur following administration of clotting factors (CFs). OBJECTIVES: To evaluate occurrence of same-day TEs for different CF products and potential risk factors. METHODS: A retrospective cohort study of individuals exposed to CF products during 2008-2013 was conducted using a large commercial insurance database. CF products were identified by procedure codes, and TEs were ascertained via diagnosis codes. Crude same-day TE rates (per 1000 persons exposed) were estimated overall and by congenital factor deficiency (CFD) status, CF products, age and gender. Multivariable logistic regression analyses were used to control for confounding. Laboratory analysis was used to compare the procoagulant activities of FIX products. RESULTS: Of 3801 individuals exposed to CFs, 117 (30.8 per 1000) had same-day TEs recorded. The crude same-day TE rate was higher for CF users without CFD, 70.2 (102 of 1452), as compared with those with CFD, 6.4 (15 of 2349) (RR, 11.0; 95% CI, 6.4-18.9). For individuals without CFD, a significantly increased same-day TE risk was identified for factor IX complex (OR, 6.92; 95% CI, 3.11-15.40), factor VIIa (OR, 9.42; 95% CI, 4.99-17.78) and other products when compared with fibrin sealant. An increased risk of a TE was found with older age (≥ 45 years), history of TEs and underlying health conditions. The laboratory identified elevated procoagulant activity in Profilnine(®) and Benefix(®) . CONCLUSIONS: The study shows an increased same-day TE risk for CF users without CFD and suggests substantial off-label CF use. The study findings also show elevated same-day TE rates for different CF products and suggest the importance of product properties and patient factors.

Febrile non-haemolytic transfusion reaction occurrence and potential risk factors among the U.S. elderly transfused in the inpatient setting, as recorded in Medicare databases during 2011-2012.

BACKGROUND AND OBJECTIVES: Febrile non-haemolytic transfusion reaction (FNHTR) is an acute transfusion complication resulting in fever, chills and/or rigours. Study's objective was to assess FNHTR occurrence and potential risk factors among inpatient U.S. elderly Medicare beneficiaries, ages 65 and older, during 2011-2012. MATERIALS AND METHODS: Our retrospective claims-based study utilized large Medicare administrative databases. FNHTR was ascertained via ICD-9-CM diagnosis code, and transfusions were identified by recorded procedure and revenue centre codes. The study ascertained FNHTR rates among the inpatient elderly overall and by age, gender, race, blood components and units transfused. Multivariate logistic regression analyses were used to assess potential risk factors. RESULTS: Among 4 336 338 inpatient transfusion stays for elderly during 2011-2012, 2517 had FNHTR diagnosis recorded, an overall rate of 58.0 per 100,000 stays. FNHTR rates (per 100,000 stays) varied by age, gender, number of units and blood components transfused. FNHTR rates were substantially higher for RBCs- and platelets-containing transfusions as compared to plasma only. Significantly higher odds of FNHTR were identified with greater number of units transfused (P < 0.01), for females vs. males (OR = 1.15, 95% CI 1.04-1.27), and with 1-year histories of transfusion (OR = 1.25, 95% CI 1.10-1.42), lymphoma (OR = 1.22, 95% CI 1.02-1.46), leukaemia (OR = 1.90, 95% CI 1.56-2.31) and other diseases. CONCLUSIONS: Our study shows increased FNHTR occurrence among elderly with greater number of units and with RBCs- and platelets-containing transfusions, suggesting need to evaluate effectiveness of prestorage leucoreduction in elderly. The study also suggests importance of prior recipient alloimmunization and underlying health conditions in the development of FNHTR.

Suppression of lipopolysaccharide-stimulated cytokine/chemokine production in skin cells by sandalwood oils and purified α-santalol and ß-santalol.

Medicinally, sandalwood oil (SO) has been attributed with antiinflammatory properties; however, mechanism(s) for this activity have not been elucidated. To examine how SOs affect inflammation, cytokine antibody arrays and enzyme-linked immunosorbent assays were used to assess changes in production of cytokines and chemokines by co-cultured human dermal fibroblasts and neo-epidermal keratinocytes exposed to lipopolysaccharides and SOs from Western Australian and East Indian sandalwood trees or to the primary SO components, α-santalol and ß-santalol. Lipopolysaccharides stimulated the release of 26 cytokines and chemokines, 20 of which were substantially suppressed by simultaneous exposure to either of the two sandalwood essential oils and to ibuprofen. The increased activity of East Indian SO correlated with increased santalol concentrations. Purified α-santalol and ß-santalol equivalently suppressed production of five indicator cytokines/chemokines at concentrations proportional to the santalol concentrations of the oils. Purified α-santalol and ß-santalol also suppressed lipopolysaccharide-induced production of the arachidonic acid metabolites, prostaglandin E2, and thromboxane B2, by the skin cell co-cultures. The ability of SOs to mimic ibuprofen non-steroidal antiinflammatory drugs that act by inhibiting cyclooxygenases suggests a possible mechanism for the observed antiinflammatory properties of topically applied SOs and provides a rationale for use in products requiring antiinflammatory effects.

Transfusion-associated circulatory overload (TACO) and potential risk factors among the inpatient US elderly as recorded in Medicare administrative databases during 2011.

BACKGROUND AND OBJECTIVES: Transfusion-associated circulatory overload (TACO) is a serious transfusion complication resulting in respiratory distress. The study's objective was to assess TACO occurrence and potential risk factors among elderly Medicare beneficiaries (ages 65 and older) in the inpatient setting during 2011. MATERIALS AND METHODS: This retrospective claims-based study utilized Medicare administrative databases in coordination with Centers for Medicare & Medicaid Services. Transfusions were identified by recorded procedure and revenue centre codes, while TACO was ascertained via ICD-9-CM diagnosis code. We evaluated TACO diagnosis code rates overall and by age, gender, race, number of units and blood components transfused. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 2,147,038 inpatient transfusion stays for elderly in 2011, 1340 had TACO diagnosis code, overall rate of 62·4 per 100,000 stays. TACO rates increased significantly with age and units transfused (P < 0·0001). After adjustment for confounding, significantly higher odds of TACO were found for women vs. men (OR = 1·40, 95% CI 1·26-1·60), White people vs. non-White people (OR = 1·38, 95% CI 1·20-1·62) and persons with congestive heart failure (OR = 1·61, 95% CI 1·44-1·88), chronic pulmonary disease (OR = 1·19, 95% CI 1·08-1·32) and different anaemias. CONCLUSION: Our study identified largest number of potential TACO cases to date and showed a substantial increase in TACO occurrence with age and number of units transfused. The study suggested increased TACO risk in elderly with congestive heart failure, chronic pulmonary disease and anaemias. Overall, study shows importance of large administrative databases as an additional epidemiological tool.

Islet cell transplantation in type 1 diabetes: an analysis of efficacy outcomes and considerations for trial designs.

To estimate treatment effect size and other parameters required for planning the designs and analyses of future phase 3 islet transplant trials, we analyzed key clinical and laboratory outcomes of 347 allogeneic islet transplant recipients, using data from the Collaborative Islet Transplant Registry (CITR). At 1 year, approximately 59% of all transplant recipients were free of severe hypoglycemic events and maintained hemoglobin A1c (HbA1c) level of ≤ 6.5%. The Kaplan-Meier (KM) survival analyses showed that 69%, 54% and 44% of these 1-year responders maintained this composite endpoint at 2, 3 and 4 years, respectively. Ninety-one percent of all recipients were free of severe hypoglycemic episodes at 1 year. Furthermore, the KM survival estimates showed that 91%, 85% and 80% of these subjects maintained this clinical benefit at 2, 3 and 4 years, respectively. These results can be very useful in developing framework for study designs, sample size estimates, and statistical analysis plans for future pivotal trials of islet cell transplantation in type 1 diabetes.

Early development of New Zealand hapuku Polyprion oxygeneios eggs and larvae.

This study describes for the first time the normal development of New Zealand hapuku Polyprion oxygeneios embryos and larvae reared from fertilization to 11 days post-hatch (dph) at a constant temperature. Fertilized eggs were obtained from natural spawnings from communally reared captive wild broodstock. Eggs averaged 2 mm in diameter and had single or multiple oil globules. Embryos developed following the main fish embryological stages and required an average of 1859·50 degree hours post-fertilization (dhpf) to hatch. The newly hatched larvae (4·86 mm mean total length, L(T) ) were undifferentiated, with unpigmented eyes, a single and simple alimentary tube and a finfold that covered the entire body. Larvae relied on the energy from the yolk-sac reserves until 11 dph (7·33 mm mean L(T) ), when yolk-sac reabsorption was almost completed. Some of the major developmental stages from hatching to yolk-sac reabsorption were eye pigmentation (5 dph), upper jaw formation (7 dph), lower jaw formation (8 dph) and mouth opening (8-9 dph). By 9 dph, the digestive system consisted of pancreas, liver, primordial stomach, anterior and posterior gut; therefore, P. oxygeneios larvae would be capable of feeding on live prey. The developmental, morphological and histological data described constitutes essential baseline information on P. oxygeneios biology and normal development.

DNA identification of ciliates associated with disease outbreaks in a New Zealand marine fish hatchery.

Ciliates associated with fish mortalities in a New Zealand hatchery were identified by DNA sequencing of the small subunit ribosomal RNA gene (SSU rRNA). Tissue samples were taken from lesions and gill tissues on freshly dead juvenile groper, brain tissue from adult kingfish, and from ciliate cultures and rotifers derived from fish mortality events between January 2007 and March 2009. Different mortality events were characterized by either of 2 ciliate species, Uronema marinum and Miamiensis avidus. A third ciliate, Mesanophrys carcini, was identified in rotifers used as food for fish larvae. Sequencing part of the SSU rRNA provided a rapid tool for the identification and monitoring of scuticociliates in the hatchery and allowed the first identification of these species in farmed fish in New Zealand.

Microbiota of plaque microcosm biofilms: effect of three times daily sucrose pulses in different simulated oral environments.

AIM: To explore the Ecological Plaque Hypothesis for dental caries. To test modification of the microbiota of dental plaque microcosm biofilms by sucrose pulsing during growth in two different simulated oral fluids, and with a urea-induced plaque pH elevation. METHODS: Plaque microcosm biofilms were cultured in an 'artificial mouth' with and without 6-min 5% w/v sucrose pulses every 8 h in an environment of continuously supplied saliva-like defined medium with mucin (DMM), or basal medium mucin (BMM, a high-peptone-yeast extract oral fluid analogue), and also in DMM + 10 mmol/l urea, with sucrose pulsing. Forty plaque species were quantified by checkerboard DNA:DNA hybridization analysis. RESULTS: Sucrose pulsing extended rapid plaque growth in DMM and BMM, inducing major microbiota changes in DMM but not in BMM. In DMM, some streptococci and lactobacilli were unaffected while others implicated in caries, together with Candida albicans and Capnocytophaga gingivalis, increased. Aerobic, microaerophilic and major anaerobic species decreased. Elevation of the pH(max) from 6.4 to 7.0 had almost no effect on the microbiota. BMM plaques were distinct from DMM plaques with particularly low levels of Candida albicans and Actinomyces. CONCLUSIONS: Modest sucrose exposure in a saliva-like environment causes profound changes in the developmental self-organization of plaque microcosms, supporting the Ecological Plaque Hypothesis. Nevertheless, there is significant stability in microbial composition with varying pH near neutrality. Increases in levels of specific bacteria in response to sucrose could be characteristic of organisms particularly important in caries.

SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies.

BACKGROUND: The variable clinical features of hereditary sensory and autonomic neuropathy (HSAN I) suggest heterogeneity. Some cases of idiopathic sensory neuropathy could be caused by missense mutations of SPTLC1 and RAB7 and not be recognised as familial. OBJECTIVE: To screen persons with dominantly inherited HSAN I and others with idiopathic sensory neuropathies for known mutations of SPTLC1 and RAB7. PATIENTS: DNA was examined from well characterised individuals of 25 kindreds with adult onset HSAN I for mutations of SPTLC1 and RAB7; 92 patients with idiopathic sensory neuropathy were also screened for known mutations of these genes. RESULTS: Of the 25 kindreds, only one had a mutation (SPTLC1 399T-->G). This kindred, and 10 without identified mutations, had prominent mutilating foot injuries with peroneal weakness. Of the remainder, 12 had foot insensitivity with injuries but no weakness, one had restless legs and burning feet, and one had dementia with hearing loss. No mutation of RAB7 was found in any of these. No known mutations of SPTLC1 or RAB7 were found in cases of idiopathic sensory neuropathy. CONCLUSIONS: Adult onset HSAN I is clinically and genetically heterogeneous and further work is required to identify additional genetic causes. Known SPTLC1or RAB7 mutations were not found in idiopathic sensory neuropathy.

Biofilm growth of Lactobacillus species is promoted by Actinomyces species and Streptococcus mutans.

The ability of oral bacteria to integrate within a biofilm is pivotal to their survival. A dependence on the amount of biofilm growth by noncoaggregating Lactobacillus rhamnosus and Lactobacillus plantarum on coculture with Actinomyces naeslundii, Actinomyces gerencseriae, Streptococcus mutans and Veillonella parvula was investigated using an artificial-mouth culture system. Biofilm formation by the lactobacilli in mono-culture was poor. In coculture with Actinomyces species the amount of L. rhamnosus increased 7-20 times and L. plantarum 4-7 times compared to its mono-culture biofilm. S. mutans also promoted substantial biofilm growth of lactobacilli but V. parvula had no effect. We conclude that these Actinomyces species promoted growth of key Lactobacillus species in a biofilm, as did S. mutans to a smaller extent, and that the ability of individual bacteria to form mono-culture biofilms is not necessarily an indicator of their survival and pathogenic potential in a complex multispecies biofilm community.

Methods for magnetically labeling stem and other cells for detection by in vivo magnetic resonance imaging.

Superparamagnetic iron oxide (SPIO) nanoparticles are being used for intracellular magnetic labeling of stem cells and other cells in order to monitor cell trafficking by magnetic resonance imaging (MRI) as part of cellular-based repair, replacement and treatment strategies. This review focuses on the various methods for magnetic labeling of stem cells and other mammalian cells and on how to translate experimental results from bench to bedside.

The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders.

BACKGROUND: Hereditary motor and sensory neuropathy type 2C (HMSN2C, Charcot-Marie-Tooth 2C [CMT2C]) is an autosomal dominant motor and sensory neuropathy involving limb, diaphragm, vocal cord, and intercostal muscles. OBJECTIVE: To identify the chromosome localization for this disorder in one large American family of English and Scottish ethnicity. METHODS: Variable clinical severity led the authors to combine several approaches to accurately identify affected patients. Genome-wide two-point linkage analysis, high-definition mapping, and multipoint and recombinant haplotype analyses were performed. Mutation analysis of the triplet repeat region of ataxin-2 was also carried out. RESULTS: The initial genome-wide scan identified a region at 12q24, and fine mapping provided a maximal lod score of 4.73 (D12S1645 and D12S1583 at theta = 0.01 and 0, respectively). With multipoint analysis, a higher lod score of 5.17 was obtained and localized to the same region at 119.0 cM. Haplotype analysis narrowed the region to approximately 5.0 cM between D12S1646,D12S1330 and D12S105,D12S1339 (12q23.3-24.21). Ataxin-2, the gene responsible for spinocerebellar ataxia type 2 (SCA2), localizes to this region, but no triplet repeat expansion or point mutations within the repeat were found. CONCLUSIONS: The gene for HMSN2C maps to 12q23-24. This region is associated with SCA2, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Further studies are needed to demonstrate the specific gene alteration and its relationship with nearby genes.

Checkerboard DNA-DNA hybridisation technology focused on the analysis of Gram-positive cariogenic bacteria.

Checkerboard DNA-DNA hybridisation enabled the quantitative analysis of plaque samples against 40 microbial species simultaneously, using digoxygenin-labelled, whole-genome DNA probes. This technique was initially developed to study the predominantly Gram-negative sub-gingival plaque microbiota. The aim of this study was to apply it to a suite of predominantly Gram-positive microorganisms, such as those implicated in cariogenesis. To specifically target Gram-positive species (and Candida albicans) required optimisation and modification of DNA extraction, prehybridisation, hybridisation, and antibody detection conditions. The suitability of the revised technique for clinical and epidemiological studies was confirmed using interproximal plaque from small groups of 5- to 6-year-old children of high (decayed, missing, or filled teeth (dmft)> or =5, n=8) and zero (n=5) caries rates.