Identifying genetic variants regulating MGMT gene expression - A study in monozygotic Danish twins.

Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient's sensitivity to therapeutic alkylating agents.

Sample size determination in method comparison and observer variability studies.

The comparison of two quantitative measuring devices is often performed with the Limits of Agreement proposed by Bland and Altman in their seminal Lancet paper back in 1986. Sample size considerations were rare for such agreement analyses in the past, but recently several proposals have been made depending on how agreement is to be assessed and the number of replicates to be used. We have summarized recent developments and recommendations in various situations including a distinction between method comparison and observer variability studies. These include current state-of-the-art analysis of and reporting guidelines for agreement studies. General recommendations close the paper.

Does diabetes modify the effect of heparin on plasma proteins? - A proteomic search for plasma protein biomarkers for diabetes-related endothelial dysfunction.

AIM: Heparin administration affects the concentrations of many plasma proteins through their displacement from the endothelial glycocalyx. A differentiated protein response in diabetes will therefore, at least partly, reflect glycocalyx changes. This study aims at identifying biomarkers of endothelial dysfunction in diabetes by statistical exploration of plasma proteome data for interactions between diabetes status and heparin treatment. METHODS: Diabetes-by-heparin interactions in relation to protein levels were inspected by regression modelling in plasma proteome data from 497 patients admitted for acute angiography. Analyses were conducted separately for all 273 proteins and as set-based analyses of 44 heparin-relevant proteins identified by gene ontology analysis and 42 heparin-influenced proteins previously reported. RESULTS: Seventy-five patients had diabetes and 361 received heparin before hospitalization. The proteome-wide analysis displayed no proteins with diabetes-heparin interaction to pass correction for multiple testing. The overall set-based analyses revealed significant association for both protein sets (p-values<2*10-4), while constraining on opposite directions of effect in diabetics and none-diabetics was insignificant (p-values = 0.11 and 0.17). CONCLUSIONS: Our plasma proteome-wide interaction approach supports that diabetes influences heparin effects on protein levels, however the direction of effects and individual proteins could not be definitively pinpointed, likely reflecting a complex protein-basis for glycocalyx dysfunction in diabetes.

Is tranexamic acid use in patients with a hip fracture safe?

AIMS: To assess the safety of tranexamic acid (TXA) in a large cohort of patients aged over 65 years who have sustained a hip fracture, with a focus on transfusion rates, mortality, and thromboembolic events. METHODS: This is a consecutive cohort study with prospectively collected registry data. Patients with a hip fracture in the Region of Southern Denmark were included over a two-year time period (2015 to 2017) with the first year constituting a control group. In the second year, perioperative TXA was introduced as an intervention. Outcome was transfusion frequency, 30-day and 90-day mortality, and thromboembolic events. The latter was defined as any diagnosis or death due to arterial or venous thrombosis. The results are presented as relative risk (RR) and hazard ratio (HR) with 95% confidence intervals (CIs). RESULTS: A total of 3,097 patients were included: 1,558 in the control group and 1,539 in the TXA group.31% (n = 477) of patients had transfusions in the control group compared to 27% (n = 405) in the TXA group yielding an adjusted RR of 0.83 (95% CI 0.75 to 0.91). TXA was not associated with increased 30-day mortality with an adjusted HR of 1.10 (95% CI 0.88 to 1.39) compared to the control group as well as no association with increased risk of 90-day mortality with a per protocol adjusted HR of 1.24 (95% CI 0.93 to 1.66). TXA was associated with a lower risk of thromboembolic events after 30 days (RR 0.63 (95% CI 0.42 to 0.93)) and 90 days (RR 0.72 (95% CI 0.52 to 0.99)). A subanalysis on haemoglobin demonstrated a median 17.7 g/L (interquartile range (IQR) 11.3 to 27.3) decrease in the control group compared to 17.7 g/L (IQR 9.7 to 25.8) in the per protocol TXA group (p = 0.060 on group level difference). CONCLUSION: TXA use in patients with a hip fracture, was not associated with an increased risk of mortality but was associated with lower transfusion rate and reduced thromboembolic events. Thus, we conclude that it is safe to use TXA in this patient group. Cite this article: Bone Joint J 2021;103-B(3):449-455.

Exposure to perfluoroalkyl substances during fetal life and hospitalization for infectious disease in childhood: A study among 1,503 children from the Odense Child Cohort.

INTRODUCTION: The immunosuppressive properties of PFASs are widely recognized. Early-life exposure to PFAS has been linked to reduced immune response to childhood vaccinations and increased rates of common infectious diseases, but implications for hospitalizations are unclear. OBJECTIVES: To investigate the association between maternal serum concentrations of five PFASs during pregnancy and the child's rate of hospitalization due to common infectious diseases between birth and 4 years of age. METHODS: Serum samples from first trimester pregnant women from the Odense Child Cohort (OCC) collected in 2010-2012 were analyzed for concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and three other PFASs. Data on child hospitalizations with an ICD-10 code for infectious disease was obtained from the Danish National Patient Register. The following were identified: upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), gastrointestinal infections (GI), and other infections. The Andersen-Gill Cox proportional hazard model for recurrent events was used to investigate the association between PFAS exposure and hospitalizations. The resulting estimates were hazard ratios (HRs), which express the relative change in the instantaneous risk of hospitalization with a doubling in maternal PFAS concentration. RESULTS: A total of 1,503 mother-child pairs were included, and 26% of the children were hospitalized at least once for infectious disease. A doubling in maternal PFOS concentration was associated with a 23% increase in the risk of hospitalization due to any infection (HR: 1.23 (95% CI: 1.05, 1.44). There was indication of an interaction between child sex and PFOS (p = 0.07) and PFDA (p = 0.06), although in opposite directions. Further, every doubling of PFOA or PFOS increased the risk of LRTI by 27% (HR: 1.27 (1.01, 1.59)) and 54% (HR: 1.54 (1.11, 2.15)), respectively. Similar tendencies were seen for URTI and the group of other infections. For GIs, the opposite pattern of association was seen as HR's were consistently below 1 (PFOA, HR: 0.55 (0.32, 0.95)). DISCUSSION: We found an association between PFOS and the overall risk of infectious disease, and between PFOS and PFOA exposures and the risk of LRTI's. These results are in agreement with previous findings from the OCC, in which maternal PFOS and PFOA concentrations were positively associated with the number of days that the children experienced fever, thereby suggesting that PFOS and PFOA may affect the prevalence of both mild and more severe infectious diseases even in a rather low-exposed population.

An Extension of the Bland-Altman Plot for Analyzing the Agreement of More than Two Raters.

The Bland-Altman plot is the most common method to analyze and visualize agreement between raters or methods of quantitative outcomes in health research. While very useful for studies with two raters, a limitation of the classical Bland-Altman plot is that it is specifically used for studies with two raters. We propose an extension of the Bland-Altman plot suitable for more than two raters and derive the approximate limits of agreement with 95% confidence intervals. We validated the suggested limit of agreement by a simulation study. Moreover, we offer suggestions on how to present bias, heterogeneity among raters, as well as the uncertainty of the limits of agreement. The resulting plot could be utilized to investigate and present agreement in studies with more than two raters.

CSF-Neurofilament Light Chain Levels in NMDAR and LGI1 Encephalitis: A National Cohort Study.

Background and Objectives: The two most common autoimmune encephalitides (AE), N-methyl-D-Aspartate receptor (NMDAR) and Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis, have been known for more than a decade. Nevertheless, no well-established biomarkers to guide treatment or estimate prognosis exist. Neurofilament light chain (NfL) has become an unspecific screening marker of axonal damage in CNS diseases, and has proven useful as a diagnostic and disease activity marker in neuroinflammatory diseases. Only limited reports on NfL in AE exist. We investigated NfL levels at diagnosis and follow-up in NMDAR and LGI1-AE patients, and evaluated the utility of CSF-NfL as a biomarker in AE. Methods: Patients were included from the National Danish AE cohort (2009-present) and diagnosed based upon autoantibody positivity and diagnostic consensus criteria. CSF-NfL was analyzed by single molecule array technology. Clinical and diagnostic information was retrospectively evaluated and related to NfL levels at baseline and follow-up. NMDAR-AE patients were subdivided into: idiopathic/teratoma associated or secondary NMDAR-AE (post-viral or concomitant with malignancies/demyelinating disease). Results: A total of 74 CSF samples from 53 AE patients (37 NMDAR and 16 LGI1 positive) were included in the study. Longitudinal CSF-NfL levels was measured in 21 patients. Median follow-up time was 23.8 and 43.9 months for NMDAR and LGI1-AE respectively. Major findings of this study are: i) CSF-NfL levels were higher in LGI1-AE than in idiopathic/teratoma associated NMDAR-AE at diagnosis; ii) CSF-NfL levels in NMDAR-AE patients distinguished idiopathic/teratoma cases from cases with other underlying etiologies (post-viral or malignancies/demyelinating diseases) and iii) Elevated CSF-NfL at diagnosis seems to be associated with worse long-term disease outcomes in both NMDAR and LGI1-AE. Discussion: CSF-NfL measurement may be beneficial as a prognostic biomarker in NMDAR and LGI1-AE, and high CSF-NfL could foster search for underlying etiologies in NMDAR-AE. Further studies on larger cohorts, using standardized methods, are warranted.

STEMI, Cardiogenic Shock, and Mortality in Patients Admitted for Acute Angiography: Associations and Predictions from Plasma Proteome Data.

AIM: Acute myocardial infarction (AMI) remains a major cause of mortality and morbidity, and cardiogenic shock (CS) a major cause of hospital mortality after AMI. Especially for ST elevation myocardial infarction (STEMI) patients, fast intervention is essential.Few proteins have proven clinically applicable for AMI. Most proposed biomarkers are based on a priori hypothesis-driven studies of single proteins, not enabling identification of novel candidates. For clinical use, the ability to predict AMI is important; however, studies of proteins in prediction models are surprisingly scarce.Consequently, we applied proteome data for identifying proteins associated with definitive STEMI, CS, and all-cause mortality after admission, and examined the ability of the proteins to predict these outcomes. METHODS AND RESULTS: Proteome-wide data of 497 patients with suspected STEMI were investigated; 381 patients were diagnosed with STEMI, 35 with CS, and 51 died during the first year. Data analysis was conducted by logistic and Cox regression modeling for association analysis, and by multivariable LASSO regression models for prediction modeling.Association studies identified 4 and 29 proteins associated with definitive STEMI or mortality, respectively. Prediction models for CS and mortality (holding two and five proteins, respectively) improved the prediction ability as compared with protein-free prediction models; AUC of 0.92 and 0.89, respectively. CONCLUSION: The association analyses propose individual proteins as putative protein biomarkers for definitive STEMI and survival after suspected STEMI, while the prediction models put forward sets of proteins with putative predicting ability of CS and survival. These proteins may be verified as biomarkers of potential clinical relevance.

Single-cell high-content imaging parameters predict functional phenotype of cultured human bone marrow stromal stem cells.

Cultured human bone marrow stromal (mesenchymal) stem cells (hBM-MSCs) are heterogenous cell populations exhibiting variable biological properties. Quantitative high-content imaging technology allows identification of morphological markers at a single cell resolution that are determinant for cellular functions. We determined the morphological characteristics of cultured primary hBM-MSCs and examined their predictive value for hBM-MSC functionality. BM-MSCs were isolated from 56 donors and characterized for their proliferative and differentiation potential. We correlated these data with cellular and nuclear morphological features determined by Operetta; a high-content imaging system. Cell area, cell geometry, and nucleus geometry of cultured hBM-MSCs exhibited significant correlation with expression of hBM-MSC membrane markers: ALP, CD146, and CD271. Proliferation capacity correlated negatively with cell and nucleus area and positively with cytoskeleton texture features. In addition, in vitro differentiation to osteoblasts as well as in vivo heterotopic bone formation was associated with decreased ratio of nucleus width to length. Multivariable analysis applying a stability selection procedure identified nuclear geometry and texture as predictors for hBM-MSCs differentiation potential to osteoblasts or adipocytes. Our data demonstrate that by employing a limited number of cell morphological characteristics, it is possible to predict the functional phenotype of cultured hBM-MSCs and thus can be used as a screening test for "quality" of hBM-MSCs prior their use in clinical protocols.

Outcome of treatment in patients with small cell lung cancer in poor performance status.

Background: Patients with small cell lung cancer (SCLC) with poor performance status (PS) especially in the elderly may not benefit from chemotherapy. The aim of this study was to compare survival of treated patients with PS 3-4 with untreated patients.Material and methods: We reviewed the medical records and pathology data for 448 patients diagnosed with small cell carcinoma from 2010 to 2015 and selected all patients in PS 3-4 for review.Results: A total of 87 patients fulfilled the inclusion criteria. Of these, 53 (61%) received chemotherapy (CT), while 34 (39%) did not. The median overall survival (OS) was 5.1 months for the treated patients and 0.7 month for the untreated (p < .001). Multivariate analysis identified lack of treatment with chemotherapy, extensive disease, and PS 4 as independent factors associated with poor prognosis, while age and gender were not. Also, patients with aged ≥70 years who had extended disease had significant improved OS when treated with CT. However, the chance of being treated with CT was significantly influenced by age.Conclusion: CT was associated with improved survival in patients with SCLC with PS 3-4 independent of age and stage of disease. Neither ED, high age, nor poor PS should be used as criteria for omitting CT.

Complication Incidences and Treatment Outcomes of Endovascular Aneurysm Repair-A Single-Center Long-Time Follow-Up Study.

BACKGROUND: Few long-time follow-up studies describe all complications, treatment outcome of complications, and mortality in relation to endovascular aneurysm repair (EVAR). The purpose of this study was to evaluate the incidence and treatment outcome including mortality of radiological visible complications related to the EVAR procedure at a single center with up to 10 years' surveillance. MATERIALS AND METHODS: Patients treated with EVAR from March 2006 to March 2016 at a Danish university hospital, 421 in total, were included. Patient and aneurysm characteristics, follow-up, and secondary intervention data were collected from a national database and medical records. Follow-up computed tomography angiography and plain abdominal X-ray reports were reviewed for complications. Scans and X-rays with suspected complications were evaluated by an interventional radiologist. RESULTS: A total of 172 complications in 147 patients, mainly in the beginning of the follow-up period, were found; 35% had a least one complication. The main part of complications (62%) was type II endoleaks, followed by stent graft stenosis (11%), type I endoleaks (9%), and stent graft occlusion (7%). A total of 66 (38%) complications, observed in 55 patients, were treated with reintervention, of which 77% were treated with endovascular procedures and 23% with surgical treatment, that is, 13% of all studied patients had a complication that required a reintervention. The remaining 2 of the 3 complications were treated conservatively. We found no increased all-cause mortality in connection with having a complication including those requiring reintervention. CONCLUSION: We presented a 10-year single-center study of EVAR. Many patients treated with EVAR had a radiological visible complication, mainly in the beginning of the follow-up period. Only a smaller fraction required reintervention and having a reintervention-requiring complication was not connected to increased mortality.

No Interaction between Polymorphisms Related to Vitamin A Metabolism and Vitamin A Intake in Relation to Colorectal Cancer in a Prospective Danish Cohort.

Although vitamin A is essential for gut immune cell trafficking (paramount for the intestinal immune system), epidemiological studies on the role of vitamin A in colorectal cancer (CRC) aetiology are conflicting. By using functional polymorphisms, gene-environment (GxE) interaction analyses may identify the biological effects (or "mechanism of action") of environmental factors on CRC aetiology. Potential interactions between dietary or supplemental vitamin A intake and genetic variation in the vitamin A metabolic pathway genes related to risk of CRC were studied. We used a nested case-cohort design within the Danish "Diet, Cancer and Health" cohort, with prospectively collected lifestyle information from 57,053 participants, and the Cox proportional hazard models and likelihood ratio test. No statistically significant associations between the selected polymorphisms and CRC, and no statistically significant interactions between vitamin A intake and the polymorphisms were found. In conclusion, no support of an involvement of vitamin A in CRC aetiology was found.

Intake of Red and Processed Meat, Use of Non-Steroid Anti-Inflammatory Drugs, Genetic Variants and Risk of Colorectal Cancer: A Prospective Study of the Danish "Diet, Cancer and Health" Cohort.

Red and processed meat have been associated with increased risk of colorectal cancer (CRC), whereas long-term use of non-steroid anti-inflammatory drugs (NSAIDs) may reduce the risk. The aim was to investigate potential interactions between meat intake, NSAID use, and gene variants in fatty acid metabolism and NSAID pathways in relation to the risk of CRC. A nested case-cohort study of 1038 CRC cases and 1857 randomly selected participants from the Danish prospective "Diet, Cancer and Health" study encompassing 57,053 persons was performed using the Cox proportional hazard model. Gene variants in SLC25A20, PRKAB1, LPCAT1, PLA2G4A, ALOX5, PTGER3, TP53, CCAT2, TCF7L2, and BCL2 were investigated. CCAT2 rs6983267 was associated with the risk of CRC per se (p < 0.01). Statistically significant interactions were found between intake of red and processed meat and CCAT2 rs6983267, TP53 rs1042522, LPCAT1 rs7737692, SLC25A20 rs7623023 (pinteraction = 0.04, 0.04, 0.02, 0.03, respectively), and the use of NSAID and alcohol intake and TP53 rs1042522 (pinteraction = 0.04, 0.04, respectively) in relation to the risk of CRC. No other consistent associations or interactions were found. This study replicated an association of CCAT2 rs6983267 with CRC and an interaction between TP53 rs1042522 and NSAID in relation to CRC. Interactions between genetic variants in fatty acid metabolism and NSAID pathways and the intake of red and processed meat were found. Our results suggest that meat intake and NSAID use affect the same carcinogenic mechanisms. All new findings should be sought replicated in independent prospective studies. Future studies on the cancer-protective effects of aspirin/NSAID should include gene and meat assessments.

Heredity of interocular similarities in components of refraction: a population-based twin study among 66- to 79-year-old female twins.

PURPOSE: To examine genetic influences on interocular similarities in ocular refraction and components of refraction among elderly female twins. METHODS: Refraction was assessed in 94 monozygotic (MZ) and 74 dizygotic (DZ) female twins aged 66-78 years. Absolute values of interocular differences (Aniso variables) in spherical refraction (SR), refractive astigmatism (AST), spherical equivalent (SE), corneal refractive power (CR), corneal astigmatism (CAST), anterior chamber depth (ACD) and axial length (AL) were calculated. The differences between sisters in each of the Aniso variables were calculated and graded into two categories, best differentiating the groups, here isometropic and anisometropic values. The cut-offs for grading as isometropic were AnisoSR < 0.75 D, AnisoAST < 0.5 D, AnisoSE < 1.0 D, AnisoCR < 0.5 D, AnisoCAST < 0.50 D, AnisoACD < 0.1 mm and AniosAL < 0.1 mm. Genetic influences on these traits were investigated by comparing the prevalence of isometropic and anisometropic differences between the MZ and DZ pairs in the Aniso variables and the interrelationships between the Aniso variables. RESULTS: When the Aniso variables were treated as continuous, no significant differences were found between the MZ and DZ subjects. When the proportions of isometropic intratwinpair interocular differences in the Aniso variables in the MZ and DZ cotwins were compared, the prevalences (MZ/DZ) were AnisoSR: 68%/60%; AnisoAST: 66%/57%; AnisoSE: 87%/68%; AnisoCR: 83%/78%; AnisoCAST: 69%/35%; AnisoACD: 77%/63%; and AnisoAL: 76%/60%. The differences were statistically significant for Aniso SE (p = 0.035, Fisher's exact test) and CAST (p = 0.007). The greater homogeneity in the interocular differences between the MZ sisters supports the assumption that isometropia of different elements of refraction is genetically influenced and tending to continue up to older ages. In cases where AnisoSE was <1.0 D, higher CR in one eye was associated with shorter AL (r = -0.398, p < 0.001), thereby contributing to emmetropization, irrespective of zygosity. In the cases of AnisoSE ≥1 D, no similar influence on emmetropization was observed. The difference between sisters in AnisoSE was associated with the intratwinpair difference in Aniso AL, but not with the intratwinpair differences in AnisoCR, irrespective of zygosity. CONCLUSION: The higher prevalence of similarities in isometropia of the spherical equivalent and corneal astigmatism between the MZ pairs compared to DZ pairs is consistent with the view that genetic influences on the refractive elements of the eye, tending to isometropia, continue into older age. The interrelation between CR and AL tends to maintain isometropia of SE irrespective of zygosity.

How to estimate mortality trends from grouped vital statistics.

BACKGROUND: Mortality data at the population level are often aggregated in age classes, for example 5-year age groups with an open-ended interval for the elderly aged 85+. Capturing detailed age-specific mortality patterns and mortality time trends from such coarsely grouped data can be problematic at older ages, especially where open-ended intervals are used. METHODS: We illustrate the penalized composite link model (PCLM) for ungrouping to model cancer mortality surfaces. Smooth age-specific distributions from data grouped in age classes of adjacent calendar years were estimated by constructing a two-dimensional regression, based on B-splines, and maximizing a penalized likelihood. We show the applicability of the proposed model, analysing age-at-death distributions from cancers of all sites in Denmark from 1980 to 2014. Data were retrieved from the Danish Cancer Society and the Human Mortality Database. RESULTS: The main trends captured by PCLM are: (i) a decrease in cancer mortality rates after the 1990s for ages 50-75; (ii) a decrease in cancer mortality in later cohorts for young ages, especially, and very advanced ages. Comparing the raw data by single year of age, with the PCLM-ungrouped distributions, we clearly illustrate that the model fits the data with a high level of accuracy. CONCLUSIONS: The PCLM produces detailed smooth mortality surfaces from death counts observed in coarse age groups with modest assumptions, that is Poisson distributed counts and smoothness of the estimated distribution. Hence, the method has great potential for use within epidemiological research when information is to be gained from aggregated data, because it avoids strict assumptions about the actual distributional shape.

Experience Applying the Guidelines for Reporting Reliability and Agreement Studies (GRRAS) Indicated Five Questions Should Be Addressed in the Planning Phase from a Statistical Point of View.

The Guidelines for Reporting Reliability and Agreement Studies (GRRAS) were proposed in 2011 to support transparent and accurate reporting. These studies may be conducted with the primary aim of estimating reliability and/or agreement itself, but are more often than not part of larger diagnostic accuracy studies, clinical trials, or epidemiological studies. As such, the study design may be compromised in terms of practicability issues, preventing the collection of sufficient results. We presented an example from a consultancy with a difficult mission and discussed five questions that concern the very nature of such a study (agreement vs. reliability; intra- vs. interrater), the rater population, explanatory factors in a multivariable model, and the statistical analysis strategy. Discussion of such basic methodological and statistical questions must take place before an investigation is started in order to ensure adequate data collection, to predict possible complications in the study, to plan sufficient statistical analyses, and to request timely assistance from an experienced statistician. GRRAS and its accompanying checklist of 15 items proved to be most helpful. Hopefully, our commentary will help improve the planning of agreement and reliability studies, which, in turn, will then be more focused, more appropriate, and more easily reported using GRRAS.

Validation of three-dimensional wound measurements using a novel 3D-WAM camera.

To monitor wound healing, it is essential to obtain accurate and reliable wound measurements. Various methods have been used to measure wound size including three-dimensional (3D) measurement devices enabling wound assessment from a volume perspective. However, the currently available methods are inaccurate, costly, or complicated to use. As a consequence, we have developed a 3D-wound assessment monitor (WAM) camera, which is able to measure wound size in three-dimension and to assess wound characteristics. The aim of the study was to assess the intrarater and interrater reliability of the 3D wound measurements using the 3D camera and to compare these with traditional measurement methods. Four raters measured 48 wounds using the 3D camera, digital imaging method (2D area), and gel injection into the wound cavity (volume). The data were analyzed using linear mixed effect model. Intraclass and interclass correlation coefficient (ICC) and Bland-Altman plots were used to assess intrarater and interrater reliability for the 3D camera and agreement between the methods. The Bland-Altman plots for intrarater reliability showed minor differences between the measurements, especially the 3D area and perimeter measurements. Moreover, ICCs were very high for both the intrarater and interrater reliability for the 2D area, 3D area, and perimeter measurements (ICCs > 0.99), although slightly lower for the volume measurements (ICC = 0.946-0.950). Finally, a high agreement was found between the 3D camera and the traditional methods (2D area and volume) assessed by narrow 95% prediction intervals and high ICCs above 0.97. In conclusion, the 3D-WAM camera is an accurate and reliable method, which is useful for several types of wounds. However, the volume measurements were primarily useful in large, deep wounds. Moreover, the 3D images are based on digital technology and therefore carry the possibility for use in remote settings.

Abdominal Aortic Aneurysms Growth Is Associated With High Concentrations of Plasma Proteins in the Intraluminal Thrombus and Diseased Arterial Tissue.

Objective- Porosity of the intraluminal thrombus (ILT) is believed to convey biologically active components from the bloodstream toward the aneurismal wall. Accumulation of molecules in the abdominal aortic aneurysmatic tissue may influence vascular protein turnover and regulate abdominal aortic aneurysm growth. We sought to identify proteins with concentrations in the ILT and the abdominal aortic aneurysm wall which associate with aneurysmal expansion rate. Approach and Results- Proteomic analysis by liquid chromatography tandem-mass spectrometry of separated wall and ILT samples was correlated with preoperative aneurysmal growth rate in 24 individuals operated electively for infrarenal abdominal aortic aneurysm. The median preoperative growth rate was 3.8 mm/y (interquartile range, 3) and the mean observational time was 3.3±1.7 years. Plasma components dominated the group of proteins with tissue concentrations, which correlate positively with growth rates ( P<0.001, Fisher exact test, both in the ILT and the wall). In contrast, in the wall and thrombus samples, ECM (extracellular matrix) proteins were significantly more prevalent in the group of proteins with negative correlations to growth rates ( P<0.05, Fisher exact test). Similarly, a long series of proteins, related to cellular functions correlated negatively to growth rates. Conclusions- When the preoperative aneurysmatic growth rate has been high, the concentration of many plasma proteins residing in the ILT and the aneurysmatic tissue is also high, compatible with the hypothesis of increased tissue porosity and accumulation of plasma components as a driver of aneurysm expansion. Moreover, many matrix and cellular proteins which are found in high concentrations in slower-growing aneurysms provides new knowledge about potential treatment targets.

Circulating microRNAs disclose biology of normal cognitive function in healthy elderly people - a discovery twin study.

Neurobiology is regulated by miRNA. Here circulating plasma miRNAs were assayed on a 754 miRNA OpenArray platform using 90 monozygotic elderly twins (73-95 year of age) and associated with mini mental state examination (MMSE) and a five-component cognitive score (CCS) in an explorative study. Both ordinary individual and twin-pair analyses were performed with level of cognitive scores. Candidate miRNAs were further associated with cognitive decline over 10 years using up to six repeated assessments. A total of 278 miRNAs were expressed in plasma from at least ten participants and 23 miRNAs were nominally associated (i.e., at an uncorrected p < 0.05) with CCS or MMSE in the paired analyses. Generally, elderly individuals with poor cognitive function had increase miRNA expression compared with equivalent individuals who performed better on the cognitive scale. Three miRNAs, miR-151a-3p, miR-212-3p and miR-1274b were associated with CCS both in the paired and the individual analysis. Four miRNAs found to be associated with CCS in cross-sectional analysis were also found to show an association in longitudinal analysis such that increase miRNA expression was associated with steeper cognitive decline. We propose a shared biological path underlies dementia and normative cognitive aging.

Choroidal thickness and myopia in relation to physical activity - the CHAMPS Eye Study.

PURPOSE: To describe the relationship between choroidal thickness (CT) and myopia in relation to physical activity (PA) in a population-based child cohort. METHODS: In a prospective study of 307 children from the CHAMPS Study Denmark, we used objective data from GT3X accelerometer worn at four periods between 2009 and 2015 to determine the amount and intensity of PA. Intensity was estimated as counts/minutes, and cut-off points were defined at four intensity levels. Eye examinations were performed in 2015 and included autorefraction in cycloplegia, axial length (AL) by biometric and fovea-centred enhanced depth imaging optical coherence tomography. By a semi-automated method, we measured the CT at 17 targets per eye representing anatomically different locations (subfoveal, 1 and 3 millimetre in each direction of fovea). RESULTS: Mean age at the eye examination was 15.4 ± 0.7 years. The mean AL was 23.5 ± 0.9 mm, and the mean subfoveal CT was 369 ± 87 µm. Choroidal thickness (CT) was 331 ± 68 µm for the overall macula, 355 ± 78 µm for the 1-mm zone and 304 ± 60 µm for the 3-mm zone. All CT measurements were thinner in myopic eyes (p < 0.0001) and in boys (p < 0.05). We found no association between total PA and the CT by either mixed model analysis (p = 0.074) or linear regression by any intensity levels (p = 0.22, p = 0.15 and p = 0.43). CONCLUSION: Among adolescents aged 14-17 years, there was no association between objective PA exposures and the CT, AL or refractive error.