Comparison of real-world treatment outcomes of systemic immunomodulating therapy in atopic dermatitis patients with dark and light skin types.

Background: Few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types. Objective: To investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type. Methods: In an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated. Results: A total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P < .001), more often had follicular eczema (22.1% vs 2.6%; P < .001), higher baseline Eczema Area and Severity Index (EASI) scores (20.1 vs 14.9; P = .009), less allergic contact dermatitis (30.9% vs 47.4%; P = .03), and less previous phototherapy use (39.7% vs 59.0%; P = .008). When comparing DST and LST corrected for covariates including baseline EASI, DST showed greater mean EASI reduction between baseline and 6 months with only dupilumab (16.7 vs 9.7; adjusted P = .032). No differences were found for adverse events for any treatments (P > .05). Limitations: Unblinded, non-randomized. Conclusion: Atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab.

Prolonged Wait Time Prior to Entry to Home Care Packages Increases the Risk of Mortality and Transition to Permanent Residential Aged Care Services: Findings from the Registry of Older South Australians (ROSA).

BACKGROUND: Older Australians prefer to live in their own homes for longer and reforms have attempted to increase the volume of home care packages (HCPs) accordingly but there remains a queue with the longer-term consequences unclear. OBJECTIVES: This study aims to characterise older Australians according to their wait times for a home care package (HCP), evaluate the association between wait time and mortality and evaluate the association between wait time and transition to permanent residential aged care services after HCP. DESIGN: A retrospective cohort study using data from the National Historical cohort (2003-2014) of the Registry of Older South Australians (ROSA) was conducted. SETTING: Home based aged care services, national cohort. METHODS: Wait time was estimated from approval date to date of receiving a HCP. Descriptive, survival estimates (95% confidence intervals (CIs)), and multivariable survival analyses (Cox-regression) were conducted to evaluate the risk of mortality and transition to permanent residential aged care services by quartiles of wait time for HCP. RESULTS: The cohort was followed for 4.0 years (interquartile range IQR (1.8-7.2)) and 38% were alive at the end of the study period with a median wait time for HCP of 62 (21-187) days. From 178,924 older people who received a HCP during the study period (2003-2013), 33.2% people received HCP within 30 days, 74.3% within 6 months and 25.7% after 6 months. The effect of wait time on risk of mortality was time-dependent, with longer wait times associated with higher mortality in the longer term. Compared to people who waited ≤30 days for a HCP, individuals who waited more than 6 months had an almost 20% excess risk of death (adjusted hazard ratio (aHR), 95%CI = (1.18, 1.16-1.21)) 2 years after entry into a HCP. Those who waited more than 6 months also had a 10% (1.10, 1.06-1.13) higher risk of transition to permanent residential aged care services after two years. CONCLUSION: Prolonged wait times for HCP is associated with a higher risk of long-term mortality as well as transition to permanent residential aged care. It remains to be seen if a shortening of this wait time translates into better health outcomes.

The Microevolution and Epidemiology of Staphylococcus aureus Colonization during Atopic Eczema Disease Flare.

Staphylococcus aureus is an opportunistic pathogen and variable component of the human microbiota. A characteristic of atopic eczema (AE) is colonization by S. aureus, with exacerbations associated with an increased bacterial burden of the organism. Despite this, the origins and genetic diversity of S. aureus colonizing individual patients during AE disease flares is poorly understood. To examine the microevolution of S. aureus colonization, we deep sequenced S. aureus populations from nine children with moderate to severe AE and 18 non-atopic children asymptomatically carrying S. aureus nasally. Colonization by clonal S. aureus populations was observed in both AE patients and control participants, with all but one of the individuals carrying colonies belonging to a single sequence type. Phylogenetic analysis showed that disease flares were associated with the clonal expansion of the S. aureus population, occurring over a period of weeks to months. There was a significant difference in the genetic backgrounds of S. aureus colonizing AE cases versus controls (Fisher exact test, P = 0.03). Examination of intra-host genetic heterogeneity of the colonizing S. aureus populations identified evidence of within-host selection in the AE patients, with AE variants being potentially selectively advantageous for intracellular persistence and treatment resistance.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Setting maximum limits for trace elements in baby food in European legislation: the outcome of International Measurement Evaluation Programme®-33.

The Institute for Reference Materials and Measurements (IRMM) of the Joint Research Centre (JRC), a Directorate-General of the European Commission, operates the International Measurement Evaluation Programme® (IMEP). It organises various types of inter-laboratory comparisons in support of European Union policies. This paper presents the results of a proficiency testing exercise (PT) focusing on the determination of total cadmium (Cd) and total lead (Pb) mass fractions in baby food in support to Commission Regulation (EC) 1881/2006 of 19 December 2006 setting maximum levels for certain contaminants in foodstuffs. The test material used in this exercise was soya-based baby food formula purchased in a local pharmacy and prepared by the Reference Materials Unit of the IRMM for this exercise. Sixty-six laboratories from 23 countries registered to the exercise and 61 of them reported results. Each participant received one bottle containing approximately 15 g of test material. Participants were asked to quantify the measurands in the powder and in the reconstituted formula. Reference values independent from the participants' results were established using isotope dilution inductively coupled plasma mass spectrometry. The total Cd mass fraction was determined by IRMM and LGC Ltd (UK), while the total Pb was determined by IRMM. The standard deviation for proficiency assessment σ^ was set at 22% of the assigned value for all measurands. Laboratories were rated with z- and ζ- (zeta) scores in accordance with ISO 13528. The outcome of this exercise is clearly influenced by the very low level of Cd and Pb content in the test material which triggered: a high number of 'less than' values; overestimated values especially for Pb very likely due to contamination; and a visible method influence in the case of Pb (methods based on atomic absorption were not sensitive enough to attain such low limits of detection). The results were also evaluated with regard to the reported limit of detection and some incoherencies were observed.

SU-E-T-112: Experimental Characterization of a Novel Thermal Reservoir for Consistent and Accurate Annealing of High-Sensitivity TLDs.

PURPOSE: To develop and characterize a novel thermal reservoir for consistent and accurate annealing of high-sensitivity thermoluminescence dosimeters (TLD-100H) for dosimetry of brachytherapy sources. METHODS: The sensitivity of TLD-100H is about 18 times that of TLD-100 which has clear advantages in for interstitial brachytherapy sources. However, the TLD-100H requires a short high temperature annealing cycle (15 min.) and opening and closing the oven door causes significant temperature fluctuations leading to unreliable measurements. A new thermal reservoir made of aluminum alloy was developed to provide stable temperature environment in a standard hot air oven. The thermal reservoir consisted of a 20 cm × 20 cm × 8 cm Al block with a machine-milled chamber in the middle to house the aluminum TLD holding tray. The thermal reservoir was placed inside the oven until it reaches thermal equilibrium with oven chamber. The temperatures of the oven chamber, heat reservoir, and TLD holding tray were monitored by two independent thermo-couples which interfaced digitally to a control computer. A LabView interface was written for monitoring and recording the temperatures in TLD holding tray, the thermal reservoir, and oven chamber. The temperature profiles were measured as a function of oven-door open duration. The settings for oven chamber temperature and oven door open-close duration were optimized to achieve a stable temperature of 240 0C in the TLD holding tray. Complete temperature profiles of the TLD annealing tray over the entire annealing process were obtained. RESULTS: A LabView interface was written for monitoring and recording the temperatures in TLD holding The use of the thermal reservoir has significantly reduced the temperature fluctuations caused by the opening of oven door when inserting the TLD holding tray into the oven chamber. It has enabled consistent annealing of high-sensitivity TLDs. CONCLUSIONS: A comprehensive characterization of a custom-built novel thermal reservoir for annealing high-sensitivity TLD has been carried out. It enabled consistent and accurate annealing of high- sensitivity TLDs which could significantly improve the efficiency of brachytherapy source characterizations. Supported in part by NIH grant R01-CA134627.

SU-E-T-92: on the Use of High-Sensitivity Thermoluminescent Dosimeters (TLDs) for Dosimetric Characterization of Low-Energy Brachytherapy Sources.

PURPOSE: To investigate the utility and accuracy of high-sensitivity TLD for dosimetric characterization of low-energy brachytherapy sources. METHODS: One hundred high-sensitivity (TLD-100H) and 100 normal-sensitivity (TLD-100) TLDs were used in this study. The TLD-100s were annealed at 400°C for one hour and then kept at room temperature for 45 minutes followed by 80°C heating for 24 hours. To prevent temperature overshot from reducing the sensitivity of TLD-100Hs, a novel thermal reservoir was built, tested, and used to anneal TLD-100H at 240 0C for 15 minutes and then kept at room temperature for 45 minutes followed by 100 0C heating for one hour. These TLDs were then irradiated uniformly in a large cavity Cs-137 irradiator for biomedical research (Shepherd, Mark III) to test their reproducibility and to establish their relative sensitivities. The radial dose function of a Model AgX100 125I source was measured using both types of TLDs in water-equivalent solid phantoms as a test case. The radial dose function measured by the TLD-100H was compared with that measured by TLD-100 to determine its utility in brachytherapy dosimetry characterization. RESULTS: Consistent and accurate annealing of high-sensitivity TLDs was achieved by using a custom-built thermal reservoir system. TLD-100H was found to be about 18 times more sensitive than TLD-100. For a 125I source with a source-strength of 2.7U, the irradiation time for radial dose function characterization up to 7 cm can be cut down from 38 days to 3 days. The radial dose function measured by TLD-100H agreed well (within ±6%) with that measured by TLD-100. CONCLUSIONS: A novel thermal reservoir was used for consistent annealing of high-sensitivity TLDs. TLD-100H can significantly shorten the irradiation time needed for a complete characterization of radial dose function. Investigation of TLD-100H for complete brachytherapy source characterization is in progress. Supported in part by NIH grant R01-CA134627.

Current trends and controversies in cutaneous melanoma.

Cutaneous melanoma is an emerging and complex health problem. Management may require the expertise of multiple specialties. Although the outlook for advanced disease remains very poor, there are major advances in the understanding of melanoma. The heterogeneous nature of melanoma is more apparent and as such it is becoming evident that in the future we will probably utilise multiple approaches to treat disease and treatments may be tailored to individual needs. We can anticipate that as technology improves and information continues to accrue, our increased understanding of melanoma will lead to improved treatment of advanced disease.

Development of a direct procedure for the measurement of sulfur isotope variability in beers by MC-ICP-MS.

In this work, a multi-collector inductively coupled plasma mass spectrometer (MC-ICP-MS) was evaluated for the direct measurement of sulfur stable isotope ratios in beers as a first step toward a general study of the natural isotope variability of sulfur in foods and beverages. Sample preparation consisted of a simple dilution of the beers with 1% (v/v) HNO(3). It was observed that different sulfur isotope ratios were obtained for different dilutions of the same sample indicating that matrix effects affected differently the transmission of the sulfur ions at masses 32, 33, and 34 in the mass spectrometer. Correction for mass bias related matrix effects was evaluated using silicon internal standardization. For that purpose, silicon isotopes at masses 29 and 30 were included in the sulfur cup configuration and the natural silicon content in beers used for internal mass bias correction. It was observed that matrix effects on differential ion transmission could be corrected adequately using silicon internal standardization. The natural isotope variability of sulfur has been evaluated by measuring 26 different beer brands. Measured delta(34)S values ranged from -0.2 to 13.8 per thousand. Typical combined standard uncertainties of the measured delta(34)S values were < or = 2 per thousand. The method has therefore great potential to study sulfur isotope variability in foods and beverages.

DNA extraction techniques for use in education.

DNA extraction provides a hands-on introduction to DNA and enables students to gain real life experience and practical knowledge of DNA. Students gain a sense of ownership and are more enthusiastic when they use their own DNA. A cost effective, simple protocol for DNA extraction and visualization was devised. Buccal mucosal epithelia provide a readily available source of cells for DNA extraction and can be harvested in a painless, noninvasive manner. Seven criteria were established to evaluate the protocol: Safety, DNA yield, DNA quality/stability, cost, user friendliness, reliability, and time. To identify the optimum conditions for each stage of the protocol (cell harvest, lysis, purification, and precipitation), each was investigated separately, and an adaptation of the fast-boiling protocol was used for the remaining stages. A validation study was undertaken with the optimized protocol to assess its performance when conducted by a group of students in a classroom setting. The optimum protocol used an isotonic Lucozade Hydro Active Fitness Water (HAFW) mouthwash. Lysis was achieved using a TE (10 mM Tris-HCl, 1 mM EDTA, pH 8) + 1% Sodium Dodecyl Sulphate (SDS) buffer. Protein was then digested using Proteinase K (Qiagen Inc., UK) at 56°C for 10 min. The DNA was then precipitated with sodium chloride and absolute ethanol. This protocol achieved an increase in DNA yield using readily available equipment and reagents at a lower per capita cost and is simple to use.

Incidence of skin cancers in 3867 patients treated with narrow-band ultraviolet B phototherapy.

BACKGROUND: Narrow-band ultraviolet B (NB-UVB) phototherapy is a widely used treatment. Psoralen-UVA photochemotherapy (PUVA) increases skin cancer risk and some animal studies have raised the possibility of an increased risk with NB-UVB. The risk of skin cancer in humans following treatment with NB-UVB is unknown. OBJECTIVES: This current analysis forms part of an ongoing study ultimately aiming to define the long-term carcinogenic risk of NB-UVB treatment in humans. METHODS: Details of all patients receiving NB-UVB treatment until 31/12/2002 in Tayside, Scotland, were accessed from a treatment database and linked to the Scottish Cancer Registry. Indirect standardization was used to compare skin cancer incidence in the study population with age and sex matched cancer registry data for the Tayside population. We also assessed the effect of NB-UVB exposure treatment numbers on the risk of developing skin cancer. RESULTS: Of 4690 records reviewed, 4665 were suitable for analysis with 3886 records linked with the cancer registry and 3867 followed-up for at least 6 months before 31/12/02 (the date at which cancer registration was deemed to be complete). The median number of NB-UVB treatments was 29 with 352 patients receiving > or = 100 treatments. The study gave 24,753 person-years of follow up. First skin cancers recorded in study patients were 27 basal cell carcinomas (BCC), seven squamous cell carcinomas (SCC) and six melanomas. No association was found between NB-UVB exposure alone (without PUVA) and any skin cancer. For NB-UVB and PUVA treated patients there was an association with BCC, with 27 BCCs found compared with 14.1 expected in the matched population. CONCLUSION: We found no significant association between NB-UVB treatment and BCC, SCC or melanoma. There was a small increase in BCCs amongst those also treated with PUVA. These reassuring results do not demonstrate the early increase in skin cancers that was found associated with PUVA treatment. However, cautious interpretation is required as the cohort contained relatively few patients who had a high treatment number and because the slow evolution of skin cancers may result in a delayed incidence peak. Ongoing risk assessment is therefore essential.

Total selenium and selenomethionine in pharmaceutical yeast tablets: assessment of the state of the art of measurement capabilities through international intercomparison CCQM-P86.

Results of an international intercomparison study (CCQM-P86) to assess the analytical capabilities of national metrology institutes (NMIs) and selected expert laboratories worldwide to accurately quantitate the mass fraction of selenomethionine (SeMet) and total Se in pharmaceutical tablets of selenised-yeast supplements (produced by Pharma Nord, Denmark) are presented. The study, jointly coordinated by LGC Ltd., UK, and the Institute for National Measurement Standards, National Research Council of Canada (NRCC), was conducted under the auspices of the Comité Consultatif pour la Quantité de Matière (CCQM) Inorganic Analysis Working Group and involved 15 laboratories (from 12 countries), of which ten were NMIs. Apart from a protocol for determination of moisture content and the provision of the certified reference material (CRM) SELM-1 to be used as the quality control sample, no sample preparation/extraction method was prescribed. A variety of approaches was thus used, including single-step and multiple-step enzymatic hydrolysis, enzymatic probe sonication and hydrolysis with methanesulfonic acid for SeMet, as well as microwave-assisted acid digestion and enzymatic probe sonication for total Se. For total Se, detection techniques included inductively coupled plasma (ICP) mass spectrometry (MS) with external calibration, standard additions or isotope dilution MS (IDMS), inductively coupled plasma optical emission spectrometry , flame atomic absorption spectrometry and instrumental neutron activation analysis. For determination of SeMet in the tablets, five NMIs and three academic/institute laboratories (of a total of five) relied upon measurements using IDMS. For species-specific IDMS measurements, an isotopically enriched standard of SeMet (76Se-enriched SeMet) was made available. A novel aspect of this study relies on the approach used to distinguish any errors which arise during analysis of a SeMet calibration solution from those which occur during analysis of the matrix. To help those participants undertaking SeMet analysis to do this, a blind sample in the form of a standard solution of natural abundance SeMet in 0.1 M HCl (with an expected value of 956 mg kg(-1) SeMet) was provided. Both high-performance liquid chromatography (HPLC)-ICP-MS or gas chromatography (GC)-ICP-MS and GC-MS techniques were used for quantitation of SeMet. Several advances in analytical methods for determination of SeMet were identified, including the combined use of double IDMS with HPLC-ICP-MS following extraction with methanesulfonic acid and simplified two-step enzymatic hydrolysis with protease/lipase/driselase followed by HPLC-ICP-IDMS, both using a species-specific IDMS approach. Overall, satisfactory agreement amongst participants was achieved; results averaged 337.6 mg kg(-1) (n = 13, with a standard deviation of 9.7 mg kg(-1)) and 561.5 mg kg(-1) (n = 11, with a standard deviation of 44.3 mg kg(-1)) with median values of 337.6 and 575.0 mg kg(-1) for total Se and SeMet, respectively. Recovery of SeMet from SELM-1 averaged 95.0% (n = 9). The ability of NMIs and expert laboratories worldwide to deliver accurate results for total Se and SeMet in such materials (selensied-yeast tablets containing approximately 300 mg kg(-1) Se) with 10% expanded uncertainty was demonstrated. The problems addressed in achieving accurate quantitation of SeMet in this product are representative of those encountered with a wide range of organometallic species in a number of common matrices.

Determination of tributyltin in marine sediment: Comité Consultatif pour la Quantité de Matière (CCQM) pilot study P-18 international intercomparison.

The capabilities of National Metrology Institutes (NMIs-those which are members of the Comité Consultatif pour la Quantité de Matière (CCQM)of the CIPM) and selected outside "expert" laboratories to quantitate (C(4)H(9))(3)Sn(+) (TBT) in a prepared marine sediment were assessed. This exercise was sanctioned by the 7th CCQM meeting, April 4-6, 2001, as an activity of the Inorganic Analysis Working Group and was jointly piloted by the Institute for National Measurement Standards of the National Research Council of Canada (NRC) and the Laboratory of the Government Chemist (LGC), UK. A total of 11 laboratories submitted results (7 NMIs, and 4 external labs). Two external laboratories utilized a standard calibration approach based on a natural abundance TBT standard, whereas all NMIs relied upon isotope dilution mass spectrometry for quantitation. For this purpose, a species specific (117)Sn-enriched TBT standard was supplied by the LGC. No sample preparation methodology was prescribed by the piloting laboratories and, by consequence, a variety of approaches was adopted by the participants, including mechanical shaking, sonication, accelerated solvent extraction, microwave assisted extraction and heating in combination with Grignard derivatization, ethylation and direct sampling. Detection techniques included ICP-MS (with GC and HPLC sample introduction), GC-MS, GC-AED and GC-FPD. Recovery of TBT from a control standard (NRCC CRM PACS-2 marine sediment) averaged 93.5+/-2.4% ( n=14). Results for the pilot material averaged 0.680+/-0.015 micro mol kg(-1) ( n=14; 80.7+/-1.8 micro g kg(-1)) with a median value of 0.676 micro mol kg(-1). Overall, performance was substantially better than state-of-the-art expectations and the satisfactory agreement amongst participants permitted scheduling of a follow-up Key comparison for TBT (K-28), a Pilot intercomparison for DBT (P-43), and certification of the test sediment for TBT content and its release as a new Certified Reference Material (HIPA-1) with a TBT content of 0.679+/-0.089 micro mol kg(-1) (expanded uncertainty, k=2, as Sn) (80.5+/-10.6 micro g kg(-1)).

Interstitial irradiation for carcinoma of the tongue and floor of mouth: Royal Marsden Hospital Experience 1970-1986.

One hundred and forty nine patients with carcinoma of the tongue or floor of mouth were treated with interstitial irradiation (+/- external beam therapy) using caesium needles or iridium wires between 1970 and 1986. Multivariate analysis showed the main predictors of outcome to be tumour stage, site and histology. Caesium and iridium techniques gave similarly good local control rates of 90% at 5 years for T1 and T2 tumours when used as the standard departmental method. Local failure was shown to have a major impact on the risk of dying from disease and elective neck irradiation (ENI) conferred a favourable benefit on neck control and survival provided the primary site was controlled. Patients less than 40 years of age appeared to have an unfavourable prognosis. Radical irradiation including interstitial techniques gives excellent results in early oral cancer and is the treatment of choice for T2 tumours. We recommend elective neck irradiation in patients at high risk of developing lymph node metastases.