Provenance of drinking water revealed through compliance sampling.

Understanding drinking water hydrochemistry is essential for maintaining safe drinking water supplies. Whilst targeted research surveys have characterised drinking water hydrochemistry, vast compliance datasets are routinely collected but are not interrogated amidst concerns regarding the impact of mixed water sources, treatment, the distribution network and customer pipework. In this paper, we examine whether compliance samples retain hydrochemical signatures of their provenance. We first created and subsequently undertook the first hydrochemical analysis of a novel national database of publically available drinking water compliance analyses (n = 3 873 941) reported for 2015 across England and Wales. k-means cluster analysis revealed three spatially coherent clusters. Cluster 1 is dominated by groundwater sources, with high nitrate concentrations and mineralisation, and lower organic carbon, residual chlorine and THM formation. Cluster 2 was dominated by surface water sources and characterised by low mineralisation (low conductivity and major ion concentrations), low nitrate and high organic carbon concentrations (and hence residual chlorine and THM formation). Cluster 3 shows a mixture of groundwater overlain by confining layers and superficial deposits (resulting in higher trace metal concentrations and mineralisation) and surface water sources. These analyses demonstrate that, despite extensive processing of drinking water, at the national scale signatures of the provenance of drinking water remain. Analysis of compliance samples is therefore likely to be a helpful tool in the characterisation of processes that may affect drinking water chemistry. The methodology used is generic and can be applied in any area where drinking water chemistry samples are taken.

The use of open source GIS algorithms, big geographic data, and cluster computing techniques to compile a geospatial database that can be used to evaluate upstream bathing and sanitation behaviours on downstream health outcomes in Indonesia, 2000-2008.

BACKGROUND: Waterborne diseases are one of the leading causes of mortality in developing countries, and diarrhea alone is responsible for over 1.5 million deaths annually. Such waterborne illnesses most often affect those in impoverished rural communities who rely on rivers for their supply of drinking water. Deaths are most common among infants and the elderly. Without knowledge of which communities are upstream of a community, upstream sanitary and bathing behaviors can never be directly linked to downstream health outcomes including disease outbreaks. Although current GIS technologies can answer the upstream question for a limited number of downstream communities, no systematic way existed of labeling each downstream village with all its upstream contributing villages along river networks or within basins at the large national scale, such as in Indonesia. This limitation prohibits macro analyses of waterborne illness across developing world communities globally. RESULTS: This novel method approach combines parallel computing, big data, community data, and open source GIS to create a database of upstream communities for 50,000-70,0000 villages in Indonesia across four differing periods. The resultant village database provides information that can be tied to the Indonesian PODES health and behavior surveys in each village to connect upstream sanitary behaviors to downstream health outcomes. We find that the approximately 250,000 communities analyzed across the four periods in Indonesia have a combined total of 13.7 million upstream villages. The average number of upstream villages per village was almost 55, the maximum number of upstream villages for any single village was over 5300. CONCLUSIONS: Advances in big-data availability, particularly high-resolution elevation data, the lowering of the cost of parallel computing options, mass survey data, and open source GIS algorithms that can utilize parallel processing and big-data, open new opportunities for the study of human health at micro granularities but across entire nations. The database generated has already been used by health researchers to compute the influence of upstream behaviors on downstream diarrhea outbreaks and to monitor avoidance behaviors to upstream water behaviors across all downstream 250,000 Indonesian villages over 4 years, and further waterborne health analyses are underway.

Additional Risk Minimisation Measures for Medicinal Products in the European Union: A Review of the Implementation and Effectiveness of Measures in the United Kingdom by One Marketing Authorisation Holder.

INTRODUCTION: Additional risk minimisation measures (aRMMs) for medicinal products are necessary to address specific important safety issues which may not be practically achieved through routine risk management measures alone. The implementation and determination of effectiveness for aRMMs can be a challenge as it involves multiple stakeholders. It is therefore important to have concise objectives to avoid undue burden on patients, healthcare professionals and the healthcare system. AIM: The aim of this study was to examine how aRMMs are implemented and how effectiveness is assessed in the European Union (EU) using practical examples from Roche Products Limited in the United Kingdom (UK) (referred to as the 'Company'). METHODS: Three centrally authorised products were selected from the Company's portfolio, each of which had aRMMs to address important safety concerns; specifically, teratogenicity, medication error and infections. The implementation of EU aRMMs, effectiveness checks and specific UK activities were analysed. Hard copy folders and electronic sites for Company aRMMs were used to assess process indicators. Periodic benefit-risk evaluation reports for specified time intervals and the Company safety database was used in checking safety outcomes for the selected products. For each product, the effectiveness of aRMMs was analysed based on specific process indicators and the subsequent safety outcomes. Literature searches were performed on scientific databases for the purposes of the broader study. RESULTS: The main process indicators in measuring effectiveness of Company aRMMs were distribution metrics for educational materials, assessment of awareness and clinical actions among healthcare professionals (HCPs). Case reports of pregnancy, medication errors and progressive multifocal leukoencephalopathy (PML) were the outcome indicators for Erivedge®â–¼, Kadcyla®â–¼ and MabThera® (the latter specifically in autoimmune indications: rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis) respectively. No pregnancy, one medication error and 10 confirmed PML cases were reported for Erivedge®â–¼, Kadcyla®â–¼ and MabThera® respectively. CONCLUSIONS: For the chosen products, a reasonable awareness of aRMMs amongst HCPs is a positive indicator of success in the use of educational materials. However, low response rates from surveys indicate that voluntary feedback may not always achieve the desired level of response in measuring effectiveness. There is a challenge in determining overall effectiveness of aRMMs due to a lack of defined success thresholds. Further regulatory guidance to outline the elements and desired outcomes of aRMMs will be useful for consistency in achieving successful outcomes.

A national-scale assessment of micro-organic contaminants in groundwater of England and Wales.

A large variety of micro-organic (MO) compounds is used in huge quantities for a range of purposes (e.g. manufacturing, food production, healthcare) and is now being frequently detected in the aquatic environment. Interest in the occurrence of MO contaminants in the terrestrial and aquatic environments continues to grow, as well as in their environmental fate and potential toxicity. However, the contamination of groundwater resources by MOs has a limited evidence base compared to other freshwater resources. Of particular concern are newly 'emerging contaminants' such as pharmaceuticals and lifestyle compounds, particularly those with potential endocrine disrupting properties. While groundwater often has a high degree of protection from pollution due to physical, chemical and biological attenuation processes in the subsurface compared to surface aquatic environments, trace concentrations of a large range of compounds are still detected in groundwater and in some cases may persist for decades due to the long residence times of groundwater systems. This study provides the first national-scale assessment of micro-organic compounds in groundwater in England and Wales. A large set of monitoring data was analysed to determine the relative occurrence and detected concentrations of different groups of compounds and to determine relationships with land-use, aquifer type and groundwater vulnerability. MOs detected including emerging compounds such as caffeine, DEET, bisphenol A, anti-microbial agents and pharmaceuticals as well as a range of legacy contaminants including chlorinated solvents and THMs, petroleum hydrocarbons, pesticides and other industrial compounds. There are clear differences in MOs between land-use types, particularly for urban-industrial and natural land-use. Temporal trends of MO occurrence are assessed but establishing long-term trends is not yet possible.

Implementing ecopharmacovigilance in practice: challenges and potential opportunities.

Ecopharmacovigilance (EPV) is a developing science and it is currently very unclear what it might mean in practice. We have performed a comparison between pharmacovigilance (PV) and EPV and have identified that there are similarities, but also some important differences that must be considered before any practical implementation of EPV. The biggest difference and greatest challenge concerns signal detection in the environment and the difficulty of identifying cause and effect. We reflect on the dramatic vulture decline in Asia, which was caused by the veterinary use of diclofenac, versus the relative difficulty in identifying the specific causes of intersex fish in European rivers. We explore what EPV might mean in practice and have identified that there are some practical measures that can be taken to assess environmental risks across product life cycle, particularly after launch of a new drug, to ensure that our risk assessments and scientific understanding of pharmaceuticals in the environment remain scientifically and ecologically relevant. These include: Tracking environmental risks after launch of the product, via literature monitoring for emerging data on exposure and effects Using Environmental Risk Management Plans (ERMPs) as a centralized resource to assess and manage the risks of a drug throughout its life cycle Further research, testing or monitoring in the environment when a risk is identified Keeping a global EPV perspective Increasing transparency and availability of environmental data for medicinal products. These measures will help to ensure that any significant environmental issues associated with pharmaceuticals in the environment (PIE) are identified in a timely way, and can be managed appropriately.

Selected national pharmacovigilance websites: an analysis of contents.

BACKGROUND: Pharmacovigilance involves the detection, assessment, understanding, and prevention of adverse drug reactions (ADRs), nationally and internationally. Effective communication, which relies increasingly on the Internet, is a crucial aspect of pharmacovigilance activities. AIM: The aim of this study was to perform an exploratory survey of national pharmacovigilance websites and compare their contents. METHODS: Of 99 international pharmacovigilance organizations known to us (listed in the Side Effects of Drugs Annual 30), 45 included website addresses and 35 provided some or all of the information in English. We reviewed 10 of these 35 websites in order to identify their contents. The 10 sites that we selected contained the most extensive information on pharmacovigilance of those that we were able to access. Reviewing these sites, we identified 32 items of information that we used to assess the scope of each website systematically, using a scoring system based on the presence or absence of those items. RESULTS: All the websites gave clear descriptions of national pharmacovigilance requirements and the reporting systems for ADRs, and all included devices. Beyond this, there was great variability in content from site to site. Few websites allowed access to raw pharmacovigilance data, such as individual case reports. CONCLUSIONS: Online drug safety communication from the selected national websites we examined is highly variable from site to site, although a wider study is needed to confirm this. Agreement on the key components of pharmacovigilance websites would facilitate the development of a standardized format to improve online communication.

Incidence, distribution, and duration of birth-related retinal hemorrhages: a prospective study.

BACKGROUND: Retinal hemorrhages secondary to birth trauma are part of the differential diagnosis of intraocular hemorrhages seen in the setting of Shaken baby syndrome in very young infants. This prospective study aimed to document the morphology, distribution and, most importantly, the natural history of these hemorrhages using digital imaging. SUBJECTS AND METHODS: Infants were recruited as soon after birth as possible and examined by indirect ophthalmoscopy. Retinal hemorrhages were photographed using the RetCam 120. Birth history was documented from the medical notes. Infants were reexamined and photographed until hemorrhages had resolved. RESULTS: Data were analyzed for a total of 53 neonates. The number of infants with retinal hemorrhage was 18 (34%). The incidence in relation to mode of delivery was as follows: vacuum delivery, 77.8%; normal vaginal delivery, 30.4%; cesarean section, 8.3%; forceps delivery, 30.3%. All hemorrhages were intraretinal and in all but two infants hemorrhages had resolved by 16 days. In two subjects hemorrhages were still present at 31 and 58 days, respectively. Both these infants were delivered by vacuum delivery. CONCLUSIONS: The RetCam 120 provides excellent documentation of retinal hemorrhages and their natural history. We have demonstrated hemorrhages still present at 58 days in a child born by vacuum delivery and this may have important implications for consideration in the differential diagnosis of Shaken baby syndrome.

Foreign body episcleral granulomas complicating intravitreal silicone oil tamponade: a clinicopathological study.

PURPOSE: To report two patients with lipid granulomas of the episclera complicating vitrectomy and silicone oil tamponade. DESIGN: Two observational case reports. INTERVENTION: Patient 1, a 41-year-old woman, underwent vitrectomy with silicone oil tamponade for proliferative diabetic retinopathy. Four weeks later, she sought treatment for inflamed episcleral nodules adjacent to one of the sclerostomy sites. The oil was removed and the episcleral nodules were excised. Patient 2, a 33-year-old man, underwent vitrectomy and silicone oil tamponade for tractional retinal detachment. He experienced a painful blind eye with episcleral nodule that required enucleation. MAIN OUTCOME MEASURES: On histopathological analysis, both specimens demonstrated episcleral granulomas caused by silicone oil. CONCLUSIONS: Episcleral nodules adjacent to vitrectomy entry sites with silicone oil tamponade may represent lipid granulomas, probably caused by silicone oil leakage from scleral entry ports.

New classification of peripheral retinal vascular changes in sickle cell disease

The systemic complications of homozygous sickle cell disease (SS) are more severe than in sickle cell haemoglobin C (SC) disease, and yet visual loss due to proliferative retinopathy is more common in the latter. This anomaly is unexplained. It is believed that proliferative disease occurs in response to closure of the peripheral retinal vasculature, yet a systematic longitudinal survey of the peripheral retinal vascular bed has not been undertaken. In the Jamaica Sickle Cohort study all subjects are scheduled to receive annual ocular examination and fluorescein angiography. The results have now been analysed in subjects with SS and SC disease using a new classificaton system based on a comparison of the peripheral retinal vascular bed with that recorded in the cohort with normal haemoglobin (AA) genotype. The vascular patterns could be classified as qualitatively normal (type I) or abnormal (type II). An abnormal vascular pattern was identified more commonly with age, in a significantly larger proportion of subjects with SC than SS disease, and was associated with the development of proliferative disease. In order to establish the dynamics of change, the angiograms were analysed in the 18 subjects (24 eyes) who developed proliferative disease. It is shown that qualitatively normal vascular pattern may be retained despited loss of capillary bed and posterior displacement of the vascular border. A border which is qualitatively abnormal does not revert to normal, and once abnormal, continuous evolution may occur before development of proliferative lesions. The peripheral border of the retinal vasculature was too peripheral to photographed in 13 of the 24 eyes before it becoming qualitatively abnormal. It is concluded that a normal border, if posterior, results from gradual modification of the capillary bed and indicated low risk of proliferative disease. A qualitatively abnormal vascular border occurs as a radical alteration of retinal perfusion in subjects in whom little modification of the vascular bed occurred before the event, and signal risk of proliferative disease. This classification system is useful in identifying the likelihood of threat to vision in young Jamaicans with sickle cell disease, and the higher frequency of proliferative retinopathy in SC can be explained by the higher prevalence of a qualitatively abnormal peripheral retinal vasculture (AU)

Peripheral retinal vasculature in normal Jamaican children

A prospective study of the peripheral retinal vasculature in a Jamaican cohort of subjects with sickle cell disease has been in progress over a period of 12 years using flourescein angiograpphy. Various vascular patterns were identified but their significance was unclear since no comparable records were available in subjects of a similar age with normal (AA) haemoglobin genotype. Fluorescein retinal angioscopy and angiography have been performed in 76 heamoglobin AA controls participating in the cohort study. The peripheral retinal capillary bed could be seen and photographed in a limited portion of the temporal peripheral fundus in a majority of this group, and there was considerable variation in the vascular pattern which could be characterised. These observations allow deviations from normal to be identified in the retinal vasculature in subjects with sickle cell disease (AU)

Sickle cell retinopathy in Jamaican children: further observations from a cohort study

Serial retinal examinations were performed in children aged 5 years and older and fluorescein angiography/angioscopy in children 6 years and older participating in a cohort study of sickle cell disease. There were 1229 patient years of observation among 389 children aged 5 - 13 years. Peripheral retinal vessel closure was present in approximately 50 percent of children with SS and SC genotypes at age 6 years and increased to affect 90 percent of children by age 12 years. A matched pair analysis, comparing groups with minimal and complete closure, indicated that complete closure was associated with significantly lower total haemoglobin and fetal haemoglobin levels and significantly lower weight in SS disease, whereas in SC disease the risk factors appeared to be high mean cell volume and low platelet count. Proliferative retinopathy was rare, occurring only once in an 8-year-old boy with SC disease, despite 592 patient years of observation in children over this age. (AU)

Recurrent visual loss in homozygous sickle cell disease

In sickle cell retinopathy vascular involvement is most frequently recognised at the retinal periphery but obstruction of perimacular arterioles and of major retinal vessels may also occur. This report describes a patient with homozygous sickle cell (SS) disease with recurrent occlusion of major retinal vessels associated with recurring transient impairment of visual function. (Summary)

Retinal changes in sickle cell/hereditary persistence of fetal haemoglobin syndrome

We describe for the first time retinal changes in sickle cell/hereditary persistence of fetal haemoglobin syndrome, which is a rare and benign disorder. The changes are qualitively similar to retinal disease seen with sickle haemoglobin and sickle C haemoglobin, but are mild (AU)

Sickle cell retinopathy in Jamaican children: a search for prognostic factors

Children with homozygous sickle cell (SS) disease and with sickle cell-haemoglobin C (SC) disease, aged 6 1/2 to 8 1/2 years, were examined by fluorescein angiography/angioscopy to determine the presence of retinal nonperfusion. The haematological and clinical features of children with and without nonperfusion were compared. Retinal vessel closure was significantly correlated with low total haemoglobin, and high fetal haemoglobin, reticulocyte, and irreversibly sickled cell counts in SS disease, and with high reticulocyte count in SC disease. No relationships were apparent between vessel closure and other haematologial indices or clinical events in either genotype (AU)

Sickle cell retinopathy in young children in Jamaica

Ophthalmological examinations were performed on 59 of the 74 (80 percent) children with homozygous sickle cell (SS) disease and on 37 of the 54 (69 percent) children with sickle cell-haemoglobin C(SC) disease, aged 5-7.5 years, within the cohort study of sickle cell disease. Arteriolar sheathing was the commonest retinal vessel abnormality, occurring in 30/59 (51 percent) SS children and in 11/37 (30 percent) SC children. Peripheral arteriolar closure was observed in 14 (24 percent) SS children and in 6 (16 percent) SC children. Arteriovenous anastomoses were seen in 3 children, but proliferative retinopathy was not identified. Capillary changes often occurred in patients without confluent closure, suggesting that complex remodelling of the capillary bed may precede retinal nonperfusion. Discrete retinal patches similar to schisis cavities resulting from intraretinal haemorrhages were found in 22 (37 percent) SS children and in 9 (24 percent) SC children, but haemorrhages were observed in only 2 patients (1 SS, 1SC). Vitreous opacities were common and were generally associated with retinal vessel disease. Retinal changes were consistently more common in children with SS disease, though the differences failed to reach statistical significance. The prevalence of peripheral vascular closure and retinal patches showed a significant upward trend with age. These observations contrast with the greater prevalence of proliferative retinopathy characterising SC disease in adults.(AU)