Paediatric Pharmacovigilance: Use of Pharmacovigilance Data Mining Algorithms for Signal Detection in a Safety Dataset of a Paediatric Clinical Study Conducted in Seven African Countries

Background

Pharmacovigilance programmes monitor and help ensuring the safe use of medicines which is critical to the success of public health programmes. The commonest method used for discovering previously unknown safety risks is spontaneous notifications. In this study we examine the use of data mining algorithms to identify signals from adverse events reported in a phase IIIb/IV clinical trial evaluating the efficacy and safety of several Artemisinin-based combination therapies (ACTs) for treatment of uncomplicated malaria in African children.

Methods

We used paediatric safety data from a multi-site, multi-country clinical study conducted in seven African countries (Burkina Faso, Gabon, Nigeria, Rwanda, Uganda, Zambia, and Mozambique). Each site compared three out of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) or chlorproguanil/dapsone and artesunate (CD+A). We examine two pharmacovigilance signal detection methods, namely proportional reporting ratio and Bayesian Confidence Propagation Neural Network on the clinical safety dataset.

Results

Among the 4,116 children (6–59 months old) enrolled and followed up for 28 days post treatment, a total of 6,238 adverse events were reported resulting into 346 drug-event combinations. Nine signals were generated both by proportional reporting ratio and Bayesian Confidence Propagation Neural Network. A review of the manufacturer package leaflets, an online Multi-Drug Symptom/Interaction Checker (DoubleCheckMD) and further by therapeutic area experts reduced the number of signals to five. The ranking of some drug-adverse reaction pairs on the basis of their signal index differed between the two methods.

Conclusions

Our two data mining methods were equally able to generate suspected signals using the pooled safety data from a phase IIIb/IV clinical trial. This analysis demonstrated the possibility of utilising clinical studies safety data for key pharmacovigilance activities like signal detection and evaluation. This approach can be applied to complement the spontaneous reporting systems which are limited by under reporting.     

Perceptions of doctors to adverse drug reaction reporting in a teaching hospital in Lagos, Nigeria

Background  

Spontaneous adverse drug reaction (ADR) reporting is the cornerstone of pharmacovigilance. ADR reporting with Yellow Cards has tremendously improved pharmacovigilance of drugs in many developed countries and its use is advocated by the World Health Organization (WHO). This study was aimed at investigating the knowledge and attitude of doctors in a teaching hospital in Lagos, Nigeria on spontaneous ADR reporting and to suggest possible ways of improving this method of reporting.     

Quality of data in the Manchester orthopaedic database.

OBJECTIVE--To determine the completeness and accuracy of data in a computerised clinical information system (Manchester orthopaedic database) in comparison with the data available through the Hospital Activity Analysis. DESIGN--Retrospective review of case notes, computer data, and Hospital Activity Analysis data. SETTING--Orthopaedic unit in a district general hospital in Manchester. SUBJECTS--200 random patient records distributed through the period of use of the computer system (1 October 1988 to 31 March 1990) and 121 records for random admissions between 1 April 1989 and 31 March 1990, 71 of which were included in the previous sample. MAIN OUTCOME MEASURES--Conformity of the computer record key words and Hospital Activity Analysis codes to an ideal key word record and ideal code record drawn up by one investigator from the clinical notes; overall quality (completeness times accuracy). RESULTS--Overall completeness of the data in the orthopaedic database was 62% and the accuracy was 96%. Completeness improved after feedback to doctors on the use of key words in regular audit meetings. Completeness was higher in inpatient than outpatient records (69.9% v 53.7%, p less than 0.001) and when a new key word was required compared with missing and incorrect key words (both p less than 0.001). Completeness was lower when the key word was required of a senior registrar (p less than 0.05). Accuracy was not significantly different. The completeness of Hospital Activity Analysis data was 90.5% and accuracy 69.5%. Thus the overall data quality was similar in both systems. CONCLUSIONS--Even in a system designed for simple and efficient data capture, compliance by users was poor. Accuracy was high, suggesting that users understood the principles of data entry. Completeness of data capture can be improved by providing feedback to users on use of the system and performance. Improvements in future versions of the software should improve performance.     

Recommended reporting items for epidemic forecasting and prediction research: The EPIFORGE 2020 guidelines

BackgroundThe importance of infectious disease epidemic forecasting and prediction research is underscored by decades of communicable disease outbreaks, including COVID-19. Unlike other fields of medical research, such as clinical trials and systematic reviews, no reporting guidelines exist for reporting epidemic forecasting and prediction research despite their utility. We therefore developed the EPIFORGE checklist, a guideline for standardized reporting of epidemic forecasting research.Methods and findingsWe developed this checklist using a best-practice process for development of reporting guidelines, involving a Delphi process and broad consultation with an international panel of infectious disease modelers and model end users. The objectives of these guidelines are to improve the consistency, reproducibility, comparability, and quality of epidemic forecasting reporting. The guidelines are not designed to advise scientists on how to perform epidemic forecasting and prediction research, but rather to serve as a standard for reporting critical methodological details of such studies.ConclusionsThese guidelines have been submitted to the EQUATOR network, in addition to hosting by other dedicated webpages to facilitate feedback and journal endorsement.

Simon Pollett and co-workers describe EPIFORGE, a guideline for reporting research on epidemic forecasting.     

Therapeutic monoclonal antibodies and the need for targeted pharmacovigilance in India

A growing number of innovative mAb therapeutics are on the global market, and biosimilar versions have now also been approved, including in India. Although efficacy and safety is demonstrated prior to approval, targeted pharmacovigilance is essential for the identification and assessment of risk for any mAb products. We analyzed the ADR data related to mAbs reported to the NCC-PvPI through the spontaneous reporting system Vigiflow during April 2011 to February 2014 to identify mAbs with the highest number of ADR including fatal/serious ADR. Only 0.72% reports were related to mAbs. Although 15 mAbs are approved in the country, only 6 mAbs were reported through Vigiflow. Rituximab was highly reported, and no fatal/serious ADR related to any mAbs were reported during the study period. Our study shows that PvPI is effective and robust system in the detection and assessment of risks associated with the use of mAbs.     

Therapeutic monoclonal antibodies and the need for targeted pharmacovigilance in India

A growing number of innovative mAb therapeutics are on the global market, and biosimilar versions have now also been approved, including in India. Although efficacy and safety is demonstrated prior to approval, targeted pharmacovigilance is essential for the identification and assessment of risk for any mAb products. We analyzed the ADR data related to mAbs reported to the NCC-PvPI through the spontaneous reporting system Vigiflow during April 2011 to February 2014 to identify mAbs with the highest number of ADR including fatal/serious ADR. Only 0.72% reports were related to mAbs. Although 15 mAbs are approved in the country, only 6 mAbs were reported through Vigiflow. Rituximab was highly reported, and no fatal/serious ADR related to any mAbs were reported during the study period. Our study shows that PvPI is effective and robust system in the detection and assessment of risks associated with the use of mAbs.     

Monitoring Important Bird Areas in Africa: Towards a Sustainable and Scaleable System

The need for effective global monitoring of biodiversity is clearer than ever, but our measurements remain patchy and inadequate. In the biodiversity-rich tropics, a central problem is the sustainability of monitoring schemes. Locally-based, participatory approaches show promise in overcoming this problem, but may not contribute effectively to monitoring at larger scales. BirdLife International’s framework for monitoring Important Bird Areas (IBAs) in Africa is designed to be simple, robust and locally-grounded, but to produce scaleable results that can be compiled into national or regional indices. Focusing on key sites for bird conservation, identified according to standard criteria, the framework institutionalises monitoring in site management authorities and Site Support Groups (community-based organisations of local people working for conservation and sustainable development). A small, central monitoring unit co-ordinates the programme nationally, compiles, analyses and manages data, and provides feedback. ‘Basic’ monitoring (taking place at all sites) involves scoring of state, pressure and response trends using site information submitted on simple forms. ‘Detailed’ monitoring (taking place at a selected sub-set of sites) involves more intensive measurement of particular variables that relate to site management targets. IBA monitoring is now underway in at least 10 African countries, with implementation of the framework most advanced (thanks to a pilot project) in Kenya. The 2004 IBA monitoring report for Kenya provides extensive information on individual IBAs, plus indices for national trends in state, pressure and response, based on data from 49 out of 60 sites. The experience in Kenya shows that institutionalisation is vital, but takes considerable time and effort; that adequate co-ordination (including timely feedback) is key; and that participatory monitoring has many valuable benefits beyond the data collected. Further work is being undertaken to refine the process, improve its scientific underpinning, and strengthen the feedback loop from data and analysis to action on the ground.     

Evidence for alternative trapping strategies in two forms of the pitcher plant, Nepenthes rafflesiana

Nepenthes pitchers are specialized leaves that function as insect traps. Several pitcher components may contribute to trapping, including the pitcher fluid, slippery wax crystals and downward-pointing epidermal cells on the inner pitcher wall, and the wetness-dependent pitcher rim (peristome), but the relative importance of these traits is unclear. Mechanisms of prey capture and retention in the field were investigated by quantifying the effect of 'knock-out' manipulations of individual pitcher structures, and by testing the ability of pitcher fluids and water to retain insects. Two forms of Nepenthes rafflesiana Jack ('elongate' and 'typical') with contrasting combinations of pitcher traits were compared. Wax crystals on the inner pitcher wall were found to be the most important trapping structure in the elongate form, whereas the typical form relied primarily on the peristome. The pitcher fluids of both forms, differing markedly in the degree of viscoelasticity, retained significantly more ants than water. The present results show that pitcher plants utilize several mechanisms for prey capture and retention, varying in efficiency and relative importance between forms. It is proposed that these differences represent alternative prey capture strategies that may provide a mechanism to reduce competition and facilitate species co-existence in nutrient-limited habitats.     

Data standards for flow cytometry

Flow cytometry (FCM) is an analytical tool widely used for cancer and HIV/AIDS research, and treatment, stem cell manipulation and detecting microorganisms in environmental samples. Current data standards do not capture the full scope of FCM experiments and there is a demand for software tools that can assist in the exploration and analysis of large FCM datasets. We are implementing a standardized approach to capturing, analyzing, and disseminating FCM data that will facilitate both more complex analyses and analysis of datasets that could not previously be efficiently studied. Initial work has focused on developing a community-based guideline for recording and reporting the details of FCM experiments. Open source software tools that implement this standard are being created, with an emphasis on facilitating reproducible and extensible data analyses. As well, tools for electronic collaboration will assist the integrated access and comprehension of experiments to empower users to collaborate on FCM analyses. This coordinated, joint development of bioinformatics standards and software tools for FCM data analysis has the potential to greatly facilitate both basic and clinical research--impacting a notably diverse range of medical and environmental research areas.     

Computerized Entry into Medical Care—Its Impact on Doctor-Patient Relationships

A large proportion of cannery workers see a doctor only as a last resort, in time of crisis. The Cannery Workers Multiphasic Screening Program identified workers in need of physician evaluation, and referred each to a physician of his choice, for examination by appointment, while the worker was not acutely ill. In many instances the screening program generated the first encounters between patient and physician. It conducted a follow-up system for workers unaccustomed to methodical health care. The program financed pretesting education of the persons to be tested, multiphasic testing, physician evaluation of abnormal findings, and the follow-up reminder system.Each physician, in advance of the appointment for evaluation, was sent a computerized report calling attention to findings that exceeded limits considered normal. The report included a form facilitating the physician''s report and billing. In counties having foundations for medical care, the foundations reviewed the form for adequacy of follow-up and appropriateness of charges.The effort to bridge the gap between findings, diagnosis and therapy, for a population group newly introduced to modern medical care delivery, was made possible by the use of the computer as a tool for the attainment of specific, preanalyzed components of the total objective.     

CliniProteus: A flexible clinical trials information management system

Clinical trials involve multi-site heterogeneous data generation with complex data input-formats and forms. The data should be captured and queried in an integrated fashion to facilitate further analysis. Electronic case-report forms (eCRF) are gaining popularity since it allows capture of clinical information in a rapid manner. We have designed and developed an XML based flexible clinical trials data management framework in .NET environment that can be used for efficient design and deployment of eCRFs to efficiently collate data and analyze information from multi-site clinical trials. The main components of our system include an XML form designer, a Patient registration eForm, reusable eForms, multiple-visit data capture and consolidated reports. A unique id is used for tracking the trial, site of occurrence, the patient and the year of recruitment.

Availability     

Modeling Within-Host Effects of Drugs on Plasmodium falciparum Transmission and Prospects for Malaria Elimination

Achieving a theoretical foundation for malaria elimination will require a detailed understanding of the quantitative relationships between patient treatment-seeking behavior, treatment coverage, and the effects of curative therapies that also block Plasmodium parasite transmission to mosquito vectors. Here, we report a mechanistic, within-host mathematical model that uses pharmacokinetic (PK) and pharmacodynamic (PD) data to simulate the effects of artemisinin-based combination therapies (ACTs) on Plasmodium falciparum transmission. To contextualize this model, we created a set of global maps of the fold reductions that would be necessary to reduce the malaria R_C (i.e. its basic reproductive number under control) to below 1 and thus interrupt transmission. This modeling was applied to low-transmission settings, defined as having a R₀<10 based on 2010 data. Our modeling predicts that treating 93–98% of symptomatic infections with an ACT within five days of fever onset would interrupt malaria transmission for ∼91% of the at-risk population of Southeast Asia and ∼74% of the global at-risk population, and lead these populations towards malaria elimination. This level of treatment coverage corresponds to an estimated 81–85% of all infected individuals in these settings. At this coverage level with ACTs, the addition of the gametocytocidal agent primaquine affords no major gains in transmission reduction. Indeed, we estimate that it would require switching ∼180 people from ACTs to ACTs plus primaquine to achieve the same transmission reduction as switching a single individual from untreated to treated with ACTs. Our model thus predicts that the addition of gametocytocidal drugs to treatment regimens provides very small population-wide benefits and that the focus of control efforts in Southeast Asia should be on increasing prompt ACT coverage. Prospects for elimination in much of Sub-Saharan Africa appear far less favorable currently, due to high rates of infection and less frequent and less rapid treatment.     

Symbiotic control of canopy dominance in subtropical and tropical forests

Subtropical and tropical forests in Asia often comprise canopy dominant trees that form symbioses with ectomycorrhizal fungi, and species-rich understorey trees that form symbioses with arbuscular mycorrhizal fungi. We propose a virtuous phosphorus acquisition hypothesis to explain this distinct structure. The hypothesis is based on (i) seedlings being rapidly colonised by ectomycorrhizal fungi from established mycelial networks that generates positive feedback and resistance to pathogens, (ii) ectomycorrhizal fungi having evolved a suite of morphological, physiological, and molecular traits to enable them to capture phosphorus from a diversity of chemical forms, including organic forms, and (iii) allocation of photosynthate carbon from adult host plants to provide the energy needed to undertake these processes.     

Interactions of transmembrane carbonic anhydrase, CAIX, with bicarbonate transporters

Association of some plasma membrane bicarbonate transporters with carbonic anhydrase enzymes forms a bicarbonate transport metabolon to facilitate metabolic CO₂-HCO₃^– conversions and coupled HCO₃^– transport. The transmembrane carbonic anhydrase, CAIX, with its extracellular catalytic site, is highly expressed in parietal and other cells of gastric mucosa, suggesting a role in acid secretion. We examined in transfected HEK293 cells the functional and physical interactions between CAIX and the parietal cell Cl^–/HCO₃^– exchanger AE2 or the putative Cl^–/HCO₃^– exchanger SLC26A7. Coexpression of CAIX increased AE2 transport activity by 28 ± 7% and also activated transport mediated by AE1 and AE3 (32 ± 10 and 37 ± 9%, respectively). In contrast, despite a transport rate comparable to that of AE3, coexpressed CAIX did not alter transport associated with SLC26A7. The CAIX-associated increase of AE2 activity did not result from altered AE2 expression or cell surface processing. CAIX was coimmunoprecipitated with the coexpressed SLC4 polypeptides AE1, AE2, and AE3, but not with SLC26A7. GST pull-down assays with a series of domain-deleted forms of CAIX revealed that the catalytic domain of CAIX mediated interaction with AE2. AE2 and CAIX colocalized in human gastric mucosa, as indicated by coimmunofluorescence. This is the first example of a functional and physical interaction between a bicarbonate transporter and a transmembrane carbonic anhydrase. We conclude that CAIX can bind to some Cl^–/HCO₃^– exchangers to form a bicarbonate transport metabolon. SLC4; SLC26; bicarbonate transport metabolon     

Skills Training of Health Workers in the Use of a Non Surgical Device (PrePex) for Adult Safe Male Circumcision

Background

Safe Male Circumcision (SMC) is a proven approach for partial protection of men from acquisition of HIV infection. Several sub-Saharan African countries have a target to circumcise 80% of males aged 15 to 49. The use of devices such as PrePex would aid scaling up of SMC. Since most health workers would have no prior experience with use of devices, skills training is needed. This paper explores a skills transfer model at an urban site in Uganda.

Objective

To assess the practicability and feasibility of rapid short duration training for safe PrePex device use.

Methods

A prospective study, conducted over 8 weeks (August–October 2012) at International Hospital Kampala, an urban Kampala hospital, examining the performance of various health worker cadres after training in the use of a non-surgical device (PrePex). The prospective study obtained approval from the Makerere School of Medicine Research and Ethics Committee and the Uganda National Council of Science and Technology. If eligible, and after the subject signed the informed consent form, they were enrolled into the study.

Results

Ten health workers were successfully trained in use of PrePex during a 3 day non-residential on-the-job training course. After the first three days of training, the trained health workers performed 561 placements and 529 device removals successfully. Over all adverse events (AE) rates were below ≤2%; however, there were some differences in AE rates across the cadres trained but not significant (p>0.25 for moderate AEs).

Conclusion

Rapid training for safe use of the PrePex device is feasible for the range of health workers available for SMC in resource limited settings, but among those with past SMC experience.     

Further consideration of phenobarbital effects on cytochrome P-450 activity in the killifish, Fundulus heteroclitus

1. Ethoxyresorufin O-deethylase (EROD) activity, aldrin epoxidase (AE) activity, cytochrome P-450 content, and levels of cytochrome P-450E (the major BNF-inducible P-450 form and primary EROD catalyst in scup) or its homologues were measured in hepatic microsomes isolated from Fundulus heteroclitus, scup (Stenotomus chrysops) and brook trout (Salvelinus fontinalis) treated with beta-naphthoflavone (BNF) or phenobarbital (PB). 2. In all three teleost species, BNF treatment caused expected increases in P-450 content, EROD activity and P-450E level; but either no change or a slight decrease in AE turnover rate (nmol/min/nmol P-450). 3. Polyclonal antibodies to P-450E did not inhibit AE activity in microsomes from BNF-treated scup, confirming that this major BNF-inducible P-450 form does not catalyze AE activity in fish. 4. In contrast, PB treatment did not affect hepatic AE activity, P-450 content or levels of "P-450E" in F. heteroclitus, but did variably affect EROD activity which was suppressed in one experiment and elevated in another. 5. The results indicate that (i) contrary to previous reports, neither PB nor MC-type inducers increase AE activity in F. heteroclitus, (ii) MC-type inducers do not affect AE activity in the other teleost species examined, and (iii) AE activity is not a reliable indicator of P-450 induction by environmental chemicals. 6. We emphasize the need to establish the mechanism of PB action, and the nature of any fish P-450 forms analogous to PB-inducible forms in mammals in order to conclusively evaluate PB-responses in fish.     

Face inversion reduces the persistence of global form and its neural correlates

Face inversion produces a detrimental effect on face recognition. The extent to which the inversion of faces and other kinds of objects influences the perceptual binding of visual information into global forms is not known. We used a behavioral method and functional MRI (fMRI) to measure the effect of face inversion on visual persistence, a type of perceptual memory that reflects sustained awareness of global form. We found that upright faces persisted longer than inverted versions of the same images; we observed a similar effect of inversion on the persistence of animal stimuli. This effect of inversion on persistence was evident in sustained fMRI activity throughout the ventral visual hierarchy, including the lateral occipital area (LO), two face-selective visual areas--the fusiform face area (FFA) and the occipital face area (OFA)--and several early visual areas. V1 showed the same initial fMRI activation to upright and inverted forms but this activation lasted longer for upright stimuli. The inversion effect on persistence-related fMRI activity in V1 and other retinotopic visual areas demonstrates that higher-tier visual areas influence early visual processing via feedback. This feedback effect on figure-ground processing is sensitive to the orientation of the figure.