Systematic literature review assessing the overall costs and societal impacts of moderate-to-severe atopic dermatitis in Europe.

Atopic dermatitis (AD) is a chronic inflammatory disease, driven by type 2 inflammation. The condition manifests as moderate-to-severe disease in approximately 20% of adults with AD across Europe and is associated with a substantial burden on patients, society and healthcare systems. However, systematic assessments capturing the totality of disease burden associated with moderate-to-severe AD are limited; therefore, the overall impacts of the disease may be underestimated. A systematic literature review (SLR) was carried out to assess the overall costs of moderate-to-severe AD across Europe, including the financial, societal and humanistic impacts. PubMed, Embase and Cochrane databases were searched to identify relevant studies published between 1 January 2010 and 2 June 2020. Scientific conference proceedings, health technology assessment websites and patient association group websites were also searched for relevant information. Twenty-seven publications, corresponding to 22 unique studies, were included in the analysis. Total costs (direct and productivity losses) reached €20 695 per-person-per-year (PPPY) for adults with uncontrolled symptoms of moderate-to-severe AD. Direct medical costs ranged between €307 and €6993 PPPY; prescription medications and specialist dermatologist visits were the main contributors. Costs increased with disease severity or with uncontrolled disease. Patients with AD also incurred personal costs of €927 per year for healthcare items not reimbursed, which increased by 9% for those with moderate-to-severe forms. Annual work productivity losses comprised most of the total costs reported for adults with moderate-to-severe AD (up to 60.8% of the total burden) and were highest in those with uncontrolled disease (€13 702 PPPY). Patients with moderate-to-severe disease also experienced physical, emotional, and social impacts. The overall costs of moderate-to-severe AD greatly impact on healthcare systems, patients and society. Sustained control of moderate-to-severe AD, through effective treatment and care management, is essential to limit the burden caused by the disease.

Molecular mechanisms of Staphylococcus aureus nasopharyngeal colonization.

Staphylococcus aureus is responsible for a wide range of different infections ranging in severity from mild to fatal. However, it primarily exists as a commensal organism in a number of different anatomical sites including the nasopharynx. Although colonization itself is a harmless state, colonized individuals are at risk of endogenous infection when S. aureus enters otherwise sterile sites via wounds or indwelling medical devices. As such, studies of colonization may identify important targets for vaccines or other prophylactic approaches. Colonization is a dynamic process; S. aureus must attach to host surfaces, overcome immune components and compete with other commensal microbes. This occurs via a number of surface-attached and secreted proteins and other factors such as wall teichoic acid. In addition, colonizing S. aureus must constantly replicate to maintain its niche and exclude other strains. These myriad interactions provide a strong selective pressure for the maintenance or enhancement of mechanisms of adhesion, invasion and immune evasion. The evolutionary implications of this may explain why S. aureus is such a capable pathogen because many of the proteins involved in colonization have also been identified as virulence factors. This review describes the diverse molecular mechanisms used by S. aureus to colonize the host and discusses how the pressures that have selected for these may have led to its virulence.

An evaluation of the USEPA calculations of greenhouse gas emissions from anaerobic lagoons.

On 10 Apr. 2009, USEPA proposed and on 30 Oct. 2009 USEPA finalized reporting thresholds for a wide range of human-derived sources of greenhouse gas (GHG) as a first step in establishing emission limits in the United States. The only on-farm source category that required monitoring under the proposed and final rule was methane (CH(4)) and nitrous oxide (NO(2)) emissions from manure storage facilities. Our objective was to assess, through a literature review, the methodology used by USEPA to estimate current CH(4) emissions from uncovered anaerobic lagoons and the proposed methodology for reporting those emissions under the proposed rule. A review of the performance of uncovered anaerobic lagoons indicates that they are more effective at degrading volatile solids (VS) than predicted using parameters provided by USEPA that had been developed for anaerobic digesters. We also documented errors in the USEPA- and International Panel on Climate Change-estimated methane conversion factors for uncovered anaerobic lagoons. We suggest estimating CH(4) emissions from anaerobic lagoons based on VS degraded in the lagoon and B' (m(3) CH(4) generated kg(-1) VS destroyed). Our estimate of CH(4) released from uncovered anaerobic lagoons indicated the regulatory operation size threshold could be at least 65% smaller than predicted by USEPA in the proposed rule. Our calculated estimate of CH(4) emissions was substantially greater than the few estimates of CH(4) loss based on direct measurements on uncovered anaerobic lagoons. More research is needed before it will be possible to provide definitive estimates of CH(4) loss from uncovered anaerobic lagoons.

Congenital glaucoma and brain stem atrophy as features of Aicardi-Goutières syndrome.

We report on three children from two families with Aicardi-Goutières syndrome. All three had congenital glaucoma. Additionally, neuroimaging demonstrated significant brain stem atrophy in the affected sib-pair. These features have not been previously described in Aicardi-Goutières syndrome and expand the phenotypic spectrum.

Innocent victim of a localised outbreak: legionella endocarditis.

Legionella pneumophila endocarditis is extremely rare. The case of a fit 26 year old man who had previously undergone homograft aortic root replacement is reported. He was admitted with legionella pneumonia during the recent localised outbreak but went on to develop endocarditis. His aortic valve was replaced with a mechanical valve and he made an uneventful recovery. Public health issues and diagnosis in susceptible patients during localised outbreaks are discussed.

A study of the toxicity of five mineral hydrocarbon waxes and oils in the F344 rat, with histological examination and tissue-specific chemical characterisation of accumulated hydrocarbon material.

Five food-grade mineral hydrocarbon (MHC) materials; a low melting point wax (LMPW), a synthetic wax (C80W) and three white oils (N15H, N70H and P70H) were administered orally to female Fischer-344 rats for 28 and 90 days at a dose level of 2% in the diet. Tissues were examined at autopsy for any treatment-related histopathological changes. The histology of target organs was the same as found in previous studies on LMPW and mineral oils and similar effects were also observed from feeding C80W. Chemical analysis showed no detectable levels of MHCs in urine and no discernible differences in the MHC profile in faeces extracts compared to diets. The presence of MHCs in most tissues was not always associated with observable histological changes. The notable observations were MHC material was detected in all tissues of rats fed with diets containing LMPW and C80W. The levels found ranged from 0.04 to 1.52% by weight for the LMPW and from 0.01 to 0.75% for the C80W. MHC material was detected in all samples of small intestine, heart and kidney for all groups. Only the livers from rats administered with LMPW and C80W were analysed, which were found to contain MHC material. Preferential accumulation of MHCs was in the alkane range approximately C(20)-C(35). The findings indicate that the size and the structure of individual components play a role both in determining their propensity to accumulate in different tissues and in the severity of any response that they elicit once they have accumulated. The implication of these findings are discussed in the context of specifications for 'food-grade' mineral hydrocarbons such as used as food additives. The data presented here suggests that the current specifications are not prescriptively adequate in controlling the amount of MHC material between C(25) and C(35) that can accumulate.

Whiplash associated disorder in children attending the emergency department.

AIMS: To determine the incidence, severity, and clinical course of whiplash associated disorder (WAD) in children aged 4-16 years involved as passengers in car crashes. METHODS: Prospective surveillance of all paediatric attendances to three English urban emergency departments after car crashes over an eight month period. An initial structured telephone interview at day 2 after the car crash was performed. This was followed by clinical review of symptomatic patients on day 5 after the crash using the Quebec Task Force criteria for outcome assessment, with subsequent clinical review at 14, 28, and 56 days or until earlier symptom resolution. RESULTS: 105 children were identified as having been involved in car crashes as passengers. Forty nine children (47%) experienced symptoms of a WAD. Twenty nine children developed symptoms within 24 hours with the remainder developing symptoms by 48 hours. Forty children experienced a WAD grade 1 and nine children suffered a WAD grade 2 injury. The mean duration of symptoms was 8.8 days (range 3-70, SD 10.7). WAD grade 2 symptoms lasted significantly longer than WAD grade 1 symptoms. CONCLUSIONS: The incidence of WAD in children in this series was higher than in other studies. The clinical course was more favourable than that reported for adults.

Assessment of intake from the diet.

Exposure assessment is one of the key parts of the risk assessment process. Only intake of toxicologically significant amounts can lead to adverse health effects even for a relatively toxic substance. In the case of chemicals in foods this is based on three major aspects: (i) how to determine quantitatively the presence of a chemical in individual foods and diets, including its fate during the processes within the food production chain; (ii) how to determine the consumption patterns of the individual foods containing the relevant chemicals; (iii) how to integrate both the likelihood of consumers eating large amounts of the given foods and of the relevant chemical being present in these foods at high levels. The techniques used for the evaluation of these three aspects have been critically reviewed in this paper to determine those areas where the current approaches provide a solid basis for assessments and those areas where improvements are needed or desirable. For those latter areas, options for improvements are being suggested, including, for example, the development of a pan-European food composition database, activities to understand better effects of processing on individual food chemicals, harmonisation of food consumption survey methods with the option of a regular pan-European survey, evaluation of probabilistic models and the development of models to assess exposure to food allergens. In all three areas, the limitations of the approaches currently used lead to uncertainties which can either cause an over- or underestimation of real intakes and thus risks. Given these imprecisions, risk assessors tend to build in additional uncertainty factors to avoid health-relevant underestimates. This is partly done by using screening methods designed to look for "worst case" situations. Such worse case assumptions lead to intake estimates that are higher than reality. These screening methods are used to screen all those chemicals with a safe intake distribution. For chemicals with a potential risk, more information is needed to allow more refined screening or even the most accurate estimation. More information and more refined methods however, require more resources. The ultimate aims are: (1) to obtain appropriate estimations for the presence and quantity of a given chemical in a food and in the diet in general; (2) to assess the consumption patterns for the foods containing these substances, including especially those parts of the population with high consumption and thus potentially high intakes; and (3) to develop and apply tools to predict reliably the likelihood of high end consumption with the presence of high levels of the relevant substances. It has thus been demonstrated that a tiered approach at all three steps can be helpful to optimise the use of the available resources: if relatively crude tools - designed to provide a "worst case" estimate - do not suggest a toxicologically significant exposure (or a relevant deficit of a particular nutrient) it may not be necessary to use more sophisticated tools. These will be needed if initially high intakes are indicated for at least parts of the population. Existing pragmatic approaches are a first crude step to model food chemical intake. It is recommended to extend, refine and validate this approach in the near future. This has to result in a cost-effective exposure assessment system to be used for existing and potential categories of chemicals. This system of knowledge (with information on sensitivities, accuracy, etc.) will guide future data collection.

The ica operon and biofilm production in coagulase-negative Staphylococci associated with carriage and disease in a neonatal intensive care unit.

Coagulase-negative staphylococci (CoNS) are a major cause of sepsis in the neonatal intensive care unit (NICU). We evaluated the hypothesis that the ica operon and biofilm production are associated with CoNS disease in this setting. CoNS associated with bacteremia or blood culture contamination and from the skin of infants with CoNS bacteremia or healthy controls were obtained during a prospective case-control study on a busy NICU. A total of 180 strains were identified, of which 122 (68%) were Staphylococcus epidermidis and the remainder were S. capitis (n = 29), S. haemolyticus (n = 11), S. hominis (n = 9), S. warneri (n = 8), and S. auricularis (n = 1). The presence of the genes icaA, icaB, icaC, and icaD was determined by PCR, and biofilm production was examined using qualitative (Congo red agar [CRA]) and quantitative (microtiter plate) techniques. There were no significant differences in the presence of the ica operon or CRA positivity among the four groups of strains. However, quantitative biofilm production was significantly greater in strains isolated from either the blood or the skin of neonates with S. epidermidis bacteremia. We conclude that the quantity of biofilm produced may be associated with the ability to cause CoNS infection. This conclusion suggests that the regulation of biofilm expression may play a central role in the disease process.

Fibronectin-binding protein A of Staphylococcus aureus has multiple, substituting, binding regions that mediate adherence to fibronectin and invasion of endothelial cells.

Invasive Staphylococcus aureus infection frequently involves bacterial seeding from the bloodstream to other body tissues, a process necessarily involving interactions between circulating bacteria and vascular endothelial cells. Staphylococcus aureus fibronectin-binding protein is central to the invasion of endothelium, fibronectin forming a bridge between bacterial fibronectin-binding proteins and host cell receptors. To dissect further the mechanisms of invasion of endothelial cells by S. aureus, a series of truncated FnBPA proteins that lacked one or more of the A, B, C or D regions were expressed on the surface of S. aureus and tested in fibronectin adhesion, endothelial cell adhesion and invasion assays. We found that this protein has multiple, substituting, fibronectin-binding regions, each capable of conferring both adherence to fibronectin and endothelial cells, and endothelial cell invasion. By expressing S. aureus FnBPA on the surface of the non-invasive Gram-positive organism Lactococcus lactis, we have found that no other bacterial factor is required for invasion. Furthermore, we have demonstrated that, as with other cell types, invasion of endothelial cells is mediated by integrin alpha5beta1. These findings may be of relevance to the development of preventive measures against systemic infection, and bacterial spread in the bacteraemic patient.

Phenotypic switching of antibiotic resistance circumvents permanent costs in Staphylococcus aureus.

Bacterial antibiotic resistance is often associated with a fitness cost in the absence of the antibiotic [1,2]. We have examined a resistance mechanism in Staphylococcus aureus that negates these costs. Exposure to gentamicin both in vitro and in vivo has been reported to result in the emergence of a gentamicin-resistant small colony variant (SCV)[3-8]. We show that the emergence of SCVs following exposure to gentamicin results from a rapid switch and that bacteria exposed to cycles of gentamicin followed by antibiotic-free medium repeatedly switched between a resistant SCV and a sensitive parental phenotype (revertants). The fitness of revertants relative to S. aureus with stable gentamicin resistance was greater in drug-free media, which suggests that S. aureus has evolved an inducible and reversible resistance mechanism that circumvents a permanent cost to fitness.

Lasers in dermatology: a review.

The revolution in laser technology has had a significant impact on medicine in general and dermatology in particular and has piqued the interest of physicians, the lay public, and the media. Advances in laser therapy have dramatically improved the clinicians' ability to treat cosmetic and noncosmetic skin lesions safely and effectively. The number and variety of skin problems amenable to laser treatment continues to grow. We will provide a review of the major cosmetic and therapeutic applications of laser therapy.

A biomarker approach to measuring human dietary exposure to certain phthalate diesters.

Three groups of eight volunteers were administered stable isotope-labelled phthalate diesters in a single dose and the amount of the corresponding phthalate monoesters excreted in the urine was measured. Amongst the phthalates administered were the symmetrical dibutyl-, di-2-ethyl- and diisooctyl- phthalates along with the unsymmetrical benzylbutylphthalate. The control group received no dose, the low dose group received 168-255 microg of each phthalate and the high dose group received 336 to 510 microg of each phthalate. The excreted phthalate monoesters were measured by LC-MS following hydrolysis of conjugates. The bulk of phthalate monoester was excreted in the first 24 hour period following the dose. For dibutylphthalate, 64% and 73% on a mole basis of the low, and high dose respectively was excreted as monobutylphthalate. For dioctylphthalate (sum of the 2-ethylhexyl and the isooctyl species) the yield was 14 and 12% of the low and high dose excreted as monooctylphthalate. For benzylbutylphthalate, 67% and 78% was eliminated as monobenzylphthalate and only 6% (measured for the high dose only) was eliminated as monobutylphthalate. These conversion factors can be used in future studies to assess exposure to phthalate esters via measuring urinary levels of the monoester metabolites.