Genetic studies require precise phenotype definitions, but electronic medical record (EMR) phenotype data are recorded inconsistently and in a variety of formats.
To present lessons learned about ...validation of EMR-based phenotypes from the Electronic Medical Records and Genomics (eMERGE) studies.
The eMERGE network created and validated 13 EMR-derived phenotype algorithms. Network sites are Group Health, Marshfield Clinic, Mayo Clinic, Northwestern University, and Vanderbilt University.
By validating EMR-derived phenotypes we learned that: (1) multisite validation improves phenotype algorithm accuracy; (2) targets for validation should be carefully considered and defined; (3) specifying time frames for review of variables eases validation time and improves accuracy; (4) using repeated measures requires defining the relevant time period and specifying the most meaningful value to be studied; (5) patient movement in and out of the health plan (transience) can result in incomplete or fragmented data; (6) the review scope should be defined carefully; (7) particular care is required in combining EMR and research data; (8) medication data can be assessed using claims, medications dispensed, or medications prescribed; (9) algorithm development and validation work best as an iterative process; and (10) validation by content experts or structured chart review can provide accurate results.
Despite the diverse structure of the five EMRs of the eMERGE sites, we developed, validated, and successfully deployed 13 electronic phenotype algorithms. Validation is a worthwhile process that not only measures phenotype performance but also strengthens phenotype algorithm definitions and enhances their inter-institutional sharing.
Polarisation-sensitive optical coherence tomography (PS-OCT) offers a novel, non-invasive method of assessing skin fibrosis in the multisystem disease systemic sclerosis (SSc) by measuring collagen ...retardance. This study aimed to assess retardance as a biomarker in SSc. Thirty-one patients with SSc and 27 healthy controls (HC) underwent PS-OCT imaging. 'Skin score' was assessed by clinical palpation (0-3 scale). A subset of ten patients and ten age/sex-matched HC had a biopsy and longitudinal imaging. Histological assessment included quantification of epidermal thickness, collagen content (to assess fibrosis) and matrix metalloproteinase (MMP) activity (in situ zymography). PS-OCT images were assessed for epidermal thickness (structure) and fibrosis (retardance). Positive correlation was observed between epidermal thickness as measured by histology and structural PS-OCT (r = 0.79; p < 0.001). Retardance was: HC mean 0.21 (SD 0.21) radian/pixel; SSc skin score 0, 0.30 (0.19); skin score 1, 0.11 (0.16); skin score 2, 0.06 (0.12); skin score 3, 0.36 (0.35). Longitudinal retardance decreased at one-week across groups, increasing at one-month for HC/skin score 0-1; HC biopsy site retardance suggests scarring is akin to fibrosis. Relationships identified between retardance with both biopsy and skin score data indicate that retardance warrants further investigation as a suitable biomarker for SSc-related fibrosis.
Knowledge about supportive care needs in patients with cutaneous invasive melanoma is scarce. We examined the unmet needs of melanoma patients treated with surgery and factors associated with these ...needs to assist health professionals identify areas needing clinical attention.
Cross-sectional multisite survey of UK patients ascertained 3 months to 5 years after complete resection of stage I–III cutaneous melanoma. Participants completed the following validated questionnaires: Supportive Care Needs Survey (SCNS-SF34 with melanoma module), Hospital Anxiety and Depression Scale and 51-item Functional Assessment of Cancer Therapy-Melanoma quality-of-life scale.
A total of 472 participants were recruited 319 (67%) clinical stage I–II). Mean age was 60 years (standard deviation = 14) and 255 (54%) were female. One hundred and twenty-three (27%) participants reported at least one unmet need (mostly ‘low’ level). The most frequently reported unmet needs were fears of cancer returning (n = 138, 29%), uncertainty about the future (n = 119, 25%), lack of information about risk of recurrence (n = 112, 24%) and about possible outcomes if melanoma were to spread (n = 91, 20%). One hundred and thirty-eight (29%) participants reported anxiety and 51 (11%) depression at clinical or subclinical levels. Patients with nodal disease had a significantly higher level of unmet supportive care needs (P < 0.001) as did patients with anxiety or depression (P < 0.001). Key correlates of the total SCNS-SF34 score for unmet supportive care needs were younger age (odds ratio, OR = 2.23, P < 0.001) and leaving school early (OR = 4.85, P < 0.001), while better emotional (OR = 0.89, P < 0.001) and social well-being (OR = 0.91, P < 0.001) were linked with fewer unmet needs. Neither patients' sex nor tumour thickness was associated with unmet needs.
Around a quarter of melanoma patients may have unmet support needs in the mid to long term after primary treatment. In particular, patients who are younger, less educated, distressed or socially isolated could benefit from more support.
The global burden of non-communicable diseases partly reflects growing exposure to ultra-processed food products (UPPs). These heavily marketed UPPs are cheap and convenient for consumers and ...profitable for manufacturers, but contain high levels of salt, fat and sugars. This study aimed to explore the potential mortality reduction associated with future policies for substantially reducing ultra-processed food intake in the UK.
We obtained data from the UK Living Cost and Food Survey and from the National Diet and Nutrition Survey. By the NOVA food typology, all food items were categorized into three groups according to the extent of food processing: Group 1 describes unprocessed/minimally processed foods. Group 2 comprises processed culinary ingredients. Group 3 includes all processed or ultra-processed products. Using UK nutrient conversion tables, we estimated the energy and nutrient profile of each food group. We then used the IMPACT Food Policy model to estimate reductions in cardiovascular mortality from improved nutrient intakes reflecting shifts from processed or ultra-processed to unprocessed/minimally processed foods. We then conducted probabilistic sensitivity analyses using Monte Carlo simulation.
Approximately 175,000 cardiovascular disease (CVD) deaths might be expected in 2030 if current mortality patterns persist. However, halving the intake of Group 3 (processed) foods could result in approximately 22,055 fewer CVD related deaths in 2030 (minimum estimate 10,705, maximum estimate 34,625). An ideal scenario in which salt and fat intakes are reduced to the low levels observed in Group 1 and 2 could lead to approximately 14,235 (minimum estimate 6,680, maximum estimate 22,525) fewer coronary deaths and approximately 7,820 (minimum estimate 4,025, maximum estimate 12,100) fewer stroke deaths, comprising almost 13% mortality reduction.
This study shows a substantial potential for reducing the cardiovascular disease burden through a healthier food system. It highlights the crucial importance of implementing healthier UK food policies.
The main objective of this investigation is to develop a chronotherapeutic drug delivery of various natural polymers based colon targeted drug delivery systems to treat early morning sign in BP. The ...polymers such as Tamarind gum, Okra gum and Chitosan were used in the formulation design. A model drug Propranolol HCl was incorporated in the formulation in order to assess the controlled release and time dependent release potential of various natural polymers. A novel polymer Tamarind gum was extracted and used as a prime polymer in this study to prove the superiority of this polymer over other leading natural polymer. Propranolol HCl was used as a model drug which undergoes hepatic metabolism and witnesses the poor bioavailability. The matrix tablets of Propranolol HCl were prepared by direct compression. The tablets were evaluated for various quality control parameters and found to be within the limits. Carbopol 940 was used as an auxiliary polymer to modify the drug release and physicochemical characteristics of the tablets. The in vitro release studies were performed in 0.1N HCl for 1.5h, followed by pH 6.8 phosphate buffer for 2h and pH 7.4 phosphate buffer till maximum amount of drug release. The in vitro release profile of the formulations were fitted with various pharmacokinetic mathematical models and analyzed for release profile. The formulations prepared with Tamarind gum prolonged the release for an extended period of time compared to other polymer based formulation and showed an excellent compression characteristic.
Objective
As a result of their complex aetiology and periodicity, dark circles are difficult to characterize and measure, with current assessment techniques relying on specialist equipment, image ...analysis or proprietary grading scales. There is therefore a need to develop and validate a photonumeric scale for assessing infraorbital dark circles, which can provide an objective and consumer relevant tool for evaluating this condition and the efficacy of treatment products and procedures.
Methods
A panel of expert clinical evaluators reviewed approximately three thousand facial photographs collected over a 5‐year period and selected images representing a dynamic range of dark circles. A 10‐point photonumeric scale was created, with corresponding descriptors and images for each grade of the scale. To rigorously validate the scale, linearity, sensitivity and precision were assessed by colorimetry and in‐clinic evaluation. Reproducibility was assessed photographically with both experienced and inexperienced clinical evaluators, whereas intragrader repeatability was assessed live in‐clinic. The scale was then employed in a split‐face randomized clinical trial on 58 subjects to evaluate the efficacy of a cosmetic treatment product over 8 weeks.
Results
Colour analysis of the images showed the scale was linear, with statistically significant correlations observed when colour data (CIElab; Individual Typology Angle) were plotted against the corresponding grades (r > 0.9, P < 0.001). Colour difference (Delta E) was calculated between the infraorbital zone and the surrounding skin, and when data were plotted against the grades, a statistically significant correlation was observed (r = 0.99, P < 0.01). The magnitude of the Delta E suggested that changes in grade are visibly perceptible to the human eye, and therefore, the scale is sensitive and clinically relevant. Intergrader reproducibility showed strong correlation (0.96) and >90% agreement between experienced evaluators, whereas intragrader repeatability assessment showed >90% perfect agreement between grades. Use of this scale in a clinical trial demonstrated the efficacy of a cosmetic product, with a mean statistically significant (P < 0.001) decrease in grade of 0.74 compared to baseline, and 0.59 versus the untreated control, after 8 weeks of treatment.
Conclusion
Our photonumeric scale for infraorbital dark circles is sensitive and robust and provides an objective and easy‐to‐use tool to evaluate dark circles and their treatment.
Résumé
Objectif
En raison de leur étiologie et de leur périodicité complexes, les cernes sont difficiles à caractériser et à mesurer, les techniques d’évaluation actuelles reposant sur des équipements spécialisés, l’analyse d’images ou des échelles de notation exclusives. Il est donc nécessaire de développer et de valider une échelle photonumérique pour évaluer les cernes infraorbitaires, laquelle peut fournir un outil objectif et pertinent pour le consommateur et tester l’efficacité des produits et des procédures de traitement.
Méthodes
Un panel d’évaluateurs cliniques experts a examiné environ trois mille photographies du visage recueillies sur une période de 5 ans, ainsi que des images sélectionnées représentant une plage dynamique de cernes. Une échelle photonumérique à 10 points a été créée, avec des descripteurs et des images correspondants à chaque grade de l’échelle. Afin de valider rigoureusement l’échelle, la linéarité, la sensibilité et la précision ont été évaluées par colorimétrie et en clinique. La reproductibilité a été évaluée sur le plan photographique par des évaluateurs cliniques expérimentés et inexpérimentés, tandis que la répétabilité intragrade a été évaluée en direct en clinique. L’échelle a ensuite été utilisée dans un essai clinique randomisé à deux parties sur 58 sujets, afin d’évaluer l’efficacité d’un produit de traitement cosmétique sur 8 semaines.
Résultats
L’analyse des couleurs des images a montré que l’échelle était linéaire, avec des corrélations statistiquement significatives observées lorsque les données de couleurs (CIElab ; angle de typologie individuel) ont été tracées par rapport aux grades correspondants (r > 0,9, P < 0,001). La différence de couleur (Delta E) a été calculée entre la zone infraorbitaire et la peau environnante, et lorsque les données ont été tracées par rapport aux grades, une corrélation statistiquement significative a été observée (r = 0,99, P < 0,01). L’ampleur du delta E a suggéré que les changements de grade sont visiblement perceptibles à l’œil humain, l’échelle étant par conséquent sensible et cliniquement pertinente. La reproductibilité intergrade a montré une forte corrélation (0,96) et une concordance > 90 % entre les évaluateurs expérimentés, tandis que l’évaluation de la répétabilité intragrade a montré une concordance parfaite > 90 % entre les grades. L’utilisation de cette échelle lors d’un essai clinique a démontré l’efficacité d’un produit cosmétique, avec une diminution moyenne statistiquement significative (P < 0,001) du grade de 0,74 par rapport à la référence, et de 0,59 par rapport au témoin non traité, après 8 semaines de traitement.
Conclusion
Notre échelle photonumérique pour les cernes infraorbitaires est sensible et robuste, fournissant un outil objectif et facile à utiliser afin d’évaluer les cernes et leur traitement.
A 10‐point photonumeric scale was created, with corresponding descriptors and images for each grade of the scale. The scale has been rigorously validated and used in a split‐face randomised clinical trial to evaluate the efficacy of a cosmetic treatment product over 8 weeks.
Background/purpose
The dermal‐epidermal junction (DEJ) forms epidermal protrusions down into the dermis (rete ridges) and dermal projections up into the epidermis (dermal papillae). Usually ...visualized in two‐dimensions (2D), our knowledge of how the DEJ changes with ageing is limited. We aimed to characterize how this structure exists in 3D and changes with age.
Methods
Photoprotected and photoexposed skin were imaged using reflectance confocal microscopy (RCM) in young and aged individuals. Biopsies of the imaged areas were processed for histological sectioning and for imaging using micro‐computed X‐ray tomography (microCT).
Results
Images obtained from RCM and microCT were used to 3D reconstruct the DEJ. DEJ heights obtained from microCT images showed strong correlation with histology‐measured heights. We proposed a novel definition of rete ridges (RRm) and dermal papillae (DPm), which allowed easier automated measurement of reduced DPm and RRm volumes in aged skin from microCT reconstructions. An algorithm to map DPm connectivity showed reduced lengths of DPm branches with age.
Conclusion
Three‐dimensional images illustrated the complex topography of the DEJ and highlighted the distinct morphology of dermal papillae compared with rete ridges, which is not evident when evaluating 2D sections. Ex vivo imaging was more successful in differentiating DEJ architecture with respect to age.
Objective
With increasing age, skin is subject to alterations in its organization, which impact on its function as well as having clinical consequences. Proteomics is a useful tool for non‐targeted, ...semi‐quantitative simultaneous investigation of high numbers of proteins. In the current study, we utilize proteomics to characterize and contrast age‐associated differences in photoexposed and photoprotected skin, with a focus on the epidermis, dermal–epidermal junction and papillary dermis.
Methods
Skin biopsies from buttock (photoprotected) and forearm (photoexposed) of healthy volunteers (aged 18–30 or ≥65 years) were transversely sectioned from the stratum corneum to a depth of 250 μm. Following SDS‐PAGE, each sample lane was segmented prior to analysis by liquid chromatography‐mass spectrometry/mass spectrometry. Pathway analysis was carried out using Ingenuity IPA.
Results
Comparison of skin proteomes at buttock and forearm sites revealed differences in relative protein abundance. Ageing in skin on the photoexposed forearm resulted in 80% of the altered proteins being increased with age, in contrast to the photoprotected buttock where 74% of altered proteins with age were reduced. Functionally, age‐altered proteins in the photoexposed forearm were associated with conferring structure, energy and metabolism. In the photoprotected buttock, proteins associated with gene expression, free‐radical scavenging, protein synthesis and protein degradation were most frequently altered.
Conclusion
This study highlights the necessity of not considering photoageing as an accelerated intrinsic ageing, but as a distinct physiological process.
Résumé
Objectif
Avec l’âge, la peau est sujette à des altérations dans son organisation, et outre le fait d'avoir des conséquences cliniques cela a un impact sur sa fonction. La protéomique est un outil utile pour l’évaluation non ciblée, semi‐quantitative, simultanée d'un nombre élevé de protéines. Dans cette étude, nous utilisons la protéomique pour caractériser et comparer les différences associées à l’âge entre une peau photoexposée et une peau photoprotégée, avec une attention particulière sur l’épiderme, la jonction dermo–épidermique et le derme papillaire.
Méthodes
Des biopsies de peau de la fesse (photoprotégée) et de l'avant‐bras (photoexposée) de volontaires sains (âgés de 18 à 30 ans ou de ≥ 65 ans) ont été sectionnées transversalement depuis la couche cornée jusqu’à une profondeur de 250 μm. Suite à une électrophorèse SDS‐PAGE, chaque échantillon a été segmenté avant l'analyse par chromatographie en phase liquide couplée à la spectrométrie de masse/spectrométrie de masse. Une analyse des voies de signalisation a été réalisée à l'aide d'Ingenuity IPA.
Résultats
La comparaison des protéomes de la peau des sites des fesses et de l'avant‐bras a révélé des différences dans l'abondance relative de protéines. Le vieillissement de la peau de l'avant‐bras photoexposée montre une augmentation de 80% des protéines altérées avec l’âge, contrairement à la peau des fesses photoprotégée où une réduction de 74 % des protéines altérées avec l’âge a été mesurée. Sur le plan de la fonction, les protéines altérées par l’âge dans la peau de l'avant‐bras photoexposée étaient associées à une structure, une énergie et un métabolisme. Dans la peau des fesses photoprotégée, les protéines associées à l'expression génique, la neutralisation des radicaux‐libres, la synthèse des protéines et la dégradation des protéines étaient le plus fréquemment altérés.
Conclusion
Cette étude souligne la nécessité de ne pas considérer le photovieillissement comme un vieillissement accéléré intrinsèque, mais comme un processus physiologique distinct.
In this study, we investigated the impact of ageing and light on the proteomes of skin collected at photoexposed and photoprotected sites. Although most of the altered proteins in skin from aged individuals were higher in abundance than in skin from younger individuals, in the photoprotected buttock the majority of the altered proteins were reduced with age. Differences in the functions of altered proteins between photoprotected and photoexposed sites also suggest that the nature of photoageing in skin may be very different and perhaps distinct from non‐photoageing.
Background
Preclinical studies demonstrated antiproliferative synergy of 1,25-D
3
(calcitriol) with cisplatin. The goals of this phase I/II study were to determine the recommended phase II dose ...(RP2D) of 1,25-D
3
with cisplatin and docetaxel and its efficacy in metastatic non-small-cell lung cancer.
Methods
Patients were ≥18 years, PS 0–1 with normal organ function. In the phase I portion, patients received escalating doses of 1,25-D
3
intravenously every 21 days prior to docetaxel 75 mg/m
2
and cisplatin 75 mg/m
2
using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate <33 %. Dose levels of 1,25-D
3
were 30, 45, 60, and 80 mcg/m
2
. A two-stage design was employed for phase II portion. We correlated
CYP24A1
tagSNPs with clinical outcome and 1,25-D
3
pharmacokinetics (PK).
Results
34 patients were enrolled. At 80 mcg/m
2
, 2/4 patients had DLTs of grade 4 neutropenia. Hypercalcemia was not observed. The RP2D of 1,25-D
3
was 60 mcg/m
2
. Among 20 evaluable phase II patients, there were 2 confirmed, 4 unconfirmed partial responses (PR), and 9 stable disease (SD). Median time to progression was 5.8 months (95 % CI 3.4, 6.5), and median overall survival 8.7 months (95 % CI 7.6, 39.4). CYP24A1 SNP rs3787554 (C > T) correlated with disease progression (
P
= 0.03) and CYP24A1 SNP rs2762939 (C > G) trended toward PR/SD (
P
= 0.08). There was no association between 1,25-D
3
PK and CYP24A1 SNPs.
Conclusions
The RP2D of 1,25-D
3
with docetaxel and cisplatin was 60 mcg/m
2
every 21 days. Pre-specified endpoint of 50 % confirmed RR was not met in the phase II study. Functional SNPs in CYP24A1 may inform future studies individualizing 1,25-D
3
.
Many nuclear components participating in related pathways appear concentrated in specific areas of the mammalian nucleus. The importance of this organization is attested to by the dysfunction that ...correlates with mis-localization of nuclear proteins in human disease and cancer. Determining the sub-nuclear localization of proteins is therefore important for understanding genome regulation and function, and it also provides clues to function for novel proteins. However, the complexity of proteins in the mammalian nucleus is too large to tackle this on a protein by protein basis. Large-scale approaches to determining protein function and sub-cellular localization are required. We have used a visual gene trap screen to identify more than 100 proteins, many of which are normal, located within compartments of the mouse nucleus. The most common discrete localizations detected are at the nucleolus and the splicing speckles and on chromosomes. Proteins at the nuclear periphery, or in other nuclear foci, have also been identified. Several of the proteins have been implicated in human disease or cancer, e.g. ATRX, HMGI-C, NBS1 and EWS, and the gene-trapped proteins provide a route into further understanding their function. We find that sequence motifs are often shared amongst proteins co-localized within the same sub-nuclear compartment. Conversely, some generally abundant motifs are lacking from the proteins concentrated in specific areas of the nucleus. This suggests that we may be able to predict sub-nuclear localization for proteins in databases based on their sequence.
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