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1.  68Ga-DOTATATE PET/CT interobserver agreement for neuroendocrine tumor assessments: results from a prospective study on 50 patients 
We evaluated the observer agreement for 68Ga-DOTATATE PET/CT study interpretations in patients with neuroendocrine tumors (NET).
Methods
68Ga-DOTATATE PET/CT was performed in 50 patients with known or suspected NET of the small bowel (n = 19), pancreas (n = 14), lung (n = 4) or other location (n = 13). Images were reviewed by seven observers who used a standardized approach for image interpretation. Observers were classified as having low (<500 scans or <5 years experience with 68Ga-DOTATATE PET/CT; n = 4) or high level of experience (≥500 scans and ≥5 years experience with 68Ga-DOTATATE PET/CT; n = 3). Interpretation by the primary nuclear medicine physician un-blinded to all clinical and imaging data served as reference standard. Interobserver agreement was determined by Cohen's κ and intraclass correlation coefficient (ICC) with corresponding 95% confidence interval (CI).
Results
Interobserver agreement was substantial and the median number of false findings (FF) was low for the overall scan result; i.e. positive versus negative study (κ = 0.80, 95%CI 0.74–0.86; FF = 3), organ involvement (κ = 0.70, 95%CI 0.64–0.76; FF = 5), and lymph node involvement (κ = 0.71, 95%CI 0.65–0.78; FF = 6). The interobserver agreement was substantial to almost-perfect and the average absolute difference (Δ) to the reference reader was low for number of organ and lymph node metastases (ICC = 0.84, 95%CI 0.77–0.89, Δ = 0.45 and ICC = 0.77, 95%CI 0.69–0.84, Δ = 0.45), tumor SUVmax (ICC = 0.99, 95%CI 0.97–0.99; Δ = 0.44) and reference SUV (SUVmean spleen: ICC = 0.81, Δ = 1.10; SUVmax liver ICC = 0.79, Δ = 0.62). Interpretations of the appropriateness for peptide-receptor radionuclide therapy (PRRT) varied more significantly among observers (κ = 0.64, 95%CI 0.57–0.70) and a higher frequency of false positive recommendations for PRRT occurred in observers with low versus high levels of experience (range, 7–12 versus 4–8).
Conclusion
The interpretation of 68Ga-DOTATATE PET/CT for NET staging is consistent among readers with low and high levels of experience. However, image based recommendations for or against PRRT require experience and training.
doi:10.2967/jnumed.116.179192
PMCID: PMC5290122  PMID: 27539839
neuroendocrine tumor; agreement; reproducibility; PET/CT; DOTATATE; interobserver
2.  Effect Estimation in Point-exposure Studies with Binary Outcomes and High-dimensional Covariate Data – a Comparison of Targeted Maximum Likelihood Estimation and Inverse Probability of Treatment Weighting 
The international journal of biostatistics  2016;12(2):/j/ijb.2016.12.issue-2/ijb-2015-0034/ijb-2015-0034.xml.
Inverse probability of treatment weighting (IPW) and targeted maximum likelihood estimation (TMLE) are relatively new methods proposed for estimating marginal causal effects. TMLE is doubly robust, yielding consistent estimators even under misspecification of either the treatment or the outcome model. While IPW methods are known to be sensitive to near violations of the practical positivity assumption (e.g., in the case of data sparsity), the consequences of this violation in the TMLE framework for binary outcomes have been less widely investigated. As near practical positivity violations are particularly likely in high-dimensional covariate settings, a better understanding of the performance of TMLE is of particular interest for pharmcoepidemiological studies using large databases.
Using plasmode and Monte-Carlo simulation studies, we evaluated the performance of TMLE compared to that of IPW estimators based on a point-exposure cohort study of the marginal causal effect of post-myocardial infarction statin use on the 1-year risk of all-cause mortality from the Clinical Practice Research Datalink. A variety of treatment model specifications were considered, inducing different degrees of near practical non-positivity.
Our simulation study showed that the performance of the TMLE and IPW estimators were comparable when the dimension of the fitted treatment model was small to moderate; however, they differed when a large number of covariates was considered. When a rich outcome model was included in the TMLE, estimators were unbiased. In some cases, we found irregular bias and large standard errors with both methods even with a correctly specified high-dimensional treatment model. The IPW estimator showed a slightly better root MSE with high-dimensional treatment model specifications in our simulation setting.
In conclusion, for estimation of the marginal expectation of the outcome under a fixed treatment, TMLE and IPW estimators employing the same treatment model specification may perform differently due to differential sensitivity to practical positivity violations; however, TMLE, being doubly robust, shows improved performance with richer specifications of the outcome model. Although TMLE is appealing for its double robustness property, such violations in a high-dimensional covariate setting are problematic for both methods.
doi:10.1515/ijb-2015-0034
PMCID: PMC5777857  PMID: 27889705 CAMSID: cams6967
Targeted Maximum Likelihood Estimation; Inverse probability weighting; Non-positivity; Doubly robust estimator; Plasmode simulation
3.  Propensity score model overfitting led to inflated variance of estimated odds ratios 
Objective
Simulation studies suggest that the ratio of the number of events to the number of estimated parameters in a logistic regression model should be not less than 10 or 20 to 1 to achieve reliable effect estimates. Applications of propensity score approaches for confounder control in practice, however, do often not consider these recommendations.
Study Design and Setting
We conducted extensive Monte Carlo and plasmode simulation studies to investigate the impact of propensity score model overfitting on the performance in estimating conditional and marginal odds ratios using different established propensity score inference approaches. We assessed estimate accuracy and precision as well as associated type I error and type II error rates in testing the null-hypothesis of no exposure effect.
Results
For all inference approaches considered, our simulation study revealed considerably inflated standard errors of effect estimates when using overfitted propensity score models. Overfitting did not considerably affect type I error rates for most inference approaches. However, because of residual confounding, estimation performance and type I error probabilities were unsatisfactory when using propensity score quintile adjustment.
Conclusion
Overfitting of propensity score models should be avoided to obtain reliable estimates of treatment or exposure effects in individual studies.
doi:10.1016/j.jclinepi.2016.05.017
PMCID: PMC5756087  PMID: 27498378 CAMSID: cams6966
propensity score; logistic regression; overfitting; confounder adjustment; odds ratio; inverse probability weighting
4.  Procedural Pain Scale Evaluation (PROPoSE) study: protocol for an evaluation of the psychometric properties of behavioural pain scales for the assessment of procedural pain in infants and children aged 6–42 months 
BMJ Open  2017;7(9):e016225.
Introduction
Infants and children are frequently exposed to painful medical procedures such as immunisation, blood sampling and intravenous access. Over 40 scales for pain assessment are available, many designed for neonatal or postoperative pain. What is not well understood is how well these scales perform when used to assess procedural pain in infants and children.
Aim
The aim of this study was to test the psychometric and practical properties of the Face, Legs, Activity, Cry and Consolability (FLACC) scale, the Modified Behavioural Pain Scale (MBPS) and the Visual Analogue Scale (VAS) observer pain scale to quantify procedural pain intensity in infants and children aged from 6–42 months to determine their suitability for clinical and research purposes.
Methods and analysis
A prospective observational non-interventional study conducted at a single centre. The psychometric and practical performance of the FLACC scale, MBPS and the VAS observer pain scale and VAS observer distress scale used to assess children experiencing procedural pain will be assessed. Infants and young children aged 6–42 months undergoing one of four painful and/or distressing procedures were recruited and the procedure digitally video recorded. Clinicians and psychologists will be recruited to independently apply the scales to these video recordings to establish intrarater and inter-rater reliability, convergent validity responsiveness and specificity. Pain score distributions will be presented descriptively; reliability will be assessed using the intraclass correlation coefficient and Bland-Altman plots. Spearman correlations will be used to assess convergence and linear mixed modelling to explore the responsiveness of the scales to pain and their capacity to distinguish between pain and distress.
Ethics and dissemination
Ethical approval was provided by the Royal Children’s Hospital Human Research Ethics Committee, approval number 35220B. The findings of this study will be disseminated via peer-reviewed journals and presented at international conferences.
doi:10.1136/bmjopen-2017-016225
PMCID: PMC5589003  PMID: 28882914
protocol; psychometric evaluation; validation; reliability; pain assessment
5.  Canadian Society of Allergy and Clinical Immunology annual scientific meeting 2016 
Alsayegh, Mohammad A. | Alshamali, Hanan | Khadada, Mousa | Ciccolini, Amanda | Ellis, Anne K. | Quint, Diana | Powley, William | Lee, Laurie | Fiteih, Yahya | Baksh, Shairaz | Vliagoftis, Harissios | Gerega, Sebastien K. | Millson, Brad | Charland, Katia | Barakat, Stephane | Sun, Xichun | Jimenez, Ricardo | Waserman, Susan | FitzGerald, Mark J. | Hébert, Jacques | Cognet-Sicé, Josiane | Renahan, Kevin E. | Huq, Saiful | Chooniedass, Rishma | Sawyer, Scott | Pasterkamp, Hans | Becker, Allan | Smith, Steven G. | Zhang, Shiyuan | Jayasundara, Kavisha | Tacon, Claire | Simidchiev, Alex | Nadeau, Gilbert | Gunsoy, Necdet | Mullerova, Hana | Albers, Frank | Kim, Young Woong | Shannon, Casey P. | Singh, Amrit | Neighbour, Helen | Larché, Mark | Tebbutt, Scott J. | Klopp, Annika | Vehling, Lorena | Becker, Allan B. | Subbarao, Padmaja | Mandhane, Piushkumar J. | Turvey, Stuart E. | Sears, Malcolm R. | Azad, Meghan B. | Loewen, Keely | Monchka, Barret | Mahmud, Salaheddin M. | Jong, Geert ‘t | Longo, Cristina | Bartlett, Gillian | Ducharme, Francine M. | Schuster, Tibor | MacGibbon, Brenda | Barnett, Tracie | North, Michelle L. | Brook, Jeff | Lee, Elizabeth | Omana, Vanessa | Thiele, Jenny | Steacy, Lisa M. | Evans, Greg | Diamond, Miriam | Sussman, Gordon L. | Amistani, Yann | Abiteboul, Kathy | Tenn, Mark W. | Yang, ChenXi | Carlsten, Christopher | Conway, Edward M. | Mack, Douglas | Othman, Yasmin | Barber, Colin M. | Kalicinsky, Chrystyna | Burke, Andrea E. | Messieh, Mary | Nair, Parameswaran | Che, Chun T. | Douglas, Lindsay | Liem, Joel | Duan, Lucy | Miller, Charlotte | Dupuis, Pascale | Connors, Lori A. | Fein, Michael N. | Shuster, Joseph | Hadi, Hani | Polk, Brooke | Raje, Nikita | Labrosse, Roxane | Bégin, Philippe | Paradis, Louis | Roches, Anne Des | Lacombe-Barrios, Jonathan | Mishra, Sanju | Lacuesta, Gina | Chiasson, Meredith | Haroon, Babar | Robertson, Kara | Issekutz, Thomas | Leddin, Desmond | Couban, Stephen | Connors, Lori | Roos, Adrienne | Kanani, Amin | Chan, Edmond S. | Schellenberg, Robert | Rosenfield, Lana | Cvetkovic, Anna | Woodward, Kevin | Quirt, Jaclyn | Watson, Wade T. A. | Castilho, Edson | Sullivan, Jennifer A. | Temple, Beverley | Martin, Donna | Cook, Victoria E. | Mills, Christopher | Portales-Casamar, Elodie | Fu, Lisa W. | Ho, Alexander | Zaltzman, Jeffrey | Chen, Lucy | Vadas, Peter | Gabrielli, Sofianne | Clarke, Ann | Eisman, Harley | Morris, Judy | Joseph, Lawrence | LaVieille, Sebastien | Ben-Shoshan, Moshe | Graham, François | Barnes, Charles | Portnoy, Jay | Stagg, Vincent | Simons, Elinor | Lefebvre, Diana | Dai, David | Mandhane, Piushkumar | Sears, Malcolm | Tam, Herman | Simons, F. Estelle R. | Alotaibi, Dhaifallah | Dawod, Bassel | Tunis, Matthew C. | Marshall, Jean | Desjardins, Marylin | Béland, Marianne | Lejtenyi, Duncan | Drolet, Jean-Phillipe | Lemire, Martine | Tsoukas, Christos | Noya, Francisco J.D. | Alizadehfar, Reza | McCusker, Christine T. | Mazer, Bruce D. | Maestre-Batlle, Danay | Gunawan, Evelyn | Rider, Christopher F. | Bølling, Anette K. | Pena, Olga M. | Suez, Daniel | Melamed, Isaac | Hussain, Iftikhar | Stein, Mark | Gupta, Sudhir | Paris, Kenneth | Fritsch, Sandor | Bourgeois, Christelle | Leibl, Heinz | McCoy, Barbara | Noel, Martin | Yel, Leman | Scott, Ori | Reid, Brenda | Atkinson, Adelle | Kim, Vy Hong-Diep | Roifman, Chaim M. | Grunebaum, Eyal | AlSelahi, Eiman | Aleman, Fernando | Oberle, Amber | Trus, Mike | Sussman, Gordon | Kanani, Amin S. | Chambenoi, Olivier | Chiva-Razavi, Sima | Grodecki, Savannah | Joshi, Nikhil | Menikefs, Peter | Holt, David | Pun, Teresa | Tworek, Damian | Hanna, Raphael | Heroux, Delia | Rosenberg, Elli | Stiemsma, Leah | Turvey, Stuart | Denburg, Judah | Mill, Christopher | Teoh, Timothy | Zimmer, Preeti | Avinashi, Vishal | Paina, Mihaela | Darwish Hassan, Ahmed A. | Oliveria, John Paul | Olesovsky, Chris | Gauvreau, Gail | Pedder, Linda | Keith, Paul K. | Plunkett, Greg | Bolner, Michelle | Pourshahnazari, Persia | Stark, Donald | Vostretsova, Kateryna | Moses, Andrew | Wakeman, Andrew | Singer, Alexander | Gerstner, Thomas | Abrams, Elissa | Johnson, Sara F. | Woodgate, Roberta L.
doi:10.1186/s13223-017-0192-y
PMCID: PMC5390240
6.  Neurodevelopmental outcome at two years of age after general and awake-regional anaesthesia in infancy: a randomised controlled trial 
Lancet (London, England)  2015;387(10015):239-250.
Summary
Background
There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here.
Methods
We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600.
Findings
Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64).
Interpretation
For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.
doi:10.1016/S0140-6736(15)00608-X
PMCID: PMC5023520  PMID: 26507180
7.  On the role of marginal confounder prevalence – implications for the high-dimensional propensity score algorithm 
Pharmacoepidemiology and drug safety  2015;24(9):1004-1007.
PURPOSE
The high-dimensional propensity score algorithm attempts to improve control of confounding in typical treatment effect studies in pharmacoepidemiology and is increasingly being used for the analysis of large administrative databases. Within this multi-step variable selection algorithm, the marginal prevalence of non-zero covariate values is considered to be an indicator for a count variable's potential confounding impact. We investigate the role of the marginal prevalence of confounder variables on potentially caused bias magnitudes when estimating risk ratios in point exposure studies with binary outcomes.
METHODS
We apply the law of total probability in conjunction with an established bias formula to derive and illustrate relative bias boundaries with respect to marginal confounder prevalence.
RESULTS
We show that maximum possible bias magnitudes can occur at any marginal prevalence level of a binary confounder variable. In particular, we demonstrate that, in case of rare or very common exposures, low and high prevalent confounder variables can still have large confounding impact on estimated risk ratios.
CONCLUSIONS
Covariate pre-selection by prevalence may lead to sub-optimal confounder sampling within the high-dimensional propensity score algorithm. While we believe that the high-dimensional propensity score has important benefits in large-scale pharmacoepidemiologic studies, we recommend omitting the prevalence-based empirical identification of candidate covariates.
doi:10.1002/pds.3773
PMCID: PMC5072887  PMID: 25866189 CAMSID: cams5890
8.  Left ventricular diastolic function is strongly correlated with active emptying of the left atrium: a novel analysis using three-dimensional echocardiography 
Background
Increased left atrial (LA) dimensions are known to be a risk factor in predicting cardiovascular events and mortality and to be one key diagnostic tool to assess diastolic dysfunction. Currently, LA measurements are usually conducted using 2D-echocardiography, although there are well-known limitations. Real-time 3D-echocardiography is able to overcome these limitations, furthermore being a valid measurement tool compared to reference standards (e.g. cardiac magnetic resonance imaging).
We investigated LA function and volume and their association to left ventricular (LV) diastolic function, using newly designed and validated software for 3D-echocardiographic analysis. This software is the first to allow for a sophisticated analysis of both passive and active LA emptying.
Methods
We analyzed 2D- and 3D-echocardiographic measurements of LA volume and function in 56 subjects and compared the results between patients with normal LV diastolic function (NDF) (n = 30, 52 ± 15 years, BMI 24.7 ± 2.6 kg/m2) and patients in which diastolic dysfunction (DDF) was suspected (n = 26, 65 ± 9 years, BMI 26.7 ± 3.7 kg/m2).
Results
Volumes during LA active emptying were significantly smaller in DDF compared to NDF (active atrial stroke volume (ASV): 3.0 (0.1–4.5) vs. 5.5 (2.7–7.8) ml, p = 0.005; True-EF: 7.3(0.1–11.5) vs. 16.2 (8.1–25.4) %, p = 0.002). Furthermore, ASV showed a stronger association to E/e’mean than all other measured LA volumes (β = − 0.35, p = 0.008). Neither total stroke LA volume, nor maximum or minimum LA volume differed significantly between the groups.
Conclusions
Diastolic LV dysfunction results in a reduction in active LA emptying, which is more strongly associated with LV filling pressure than other previously investigated LA parameters.
doi:10.1186/s12947-016-0085-0
PMCID: PMC5055675  PMID: 27717383
Three-dimensional echocardiography; Left atrium; Left ventricular diastolic function
9.  The performance of different propensity score methods for estimating absolute effects of treatments on survival outcomes: A simulation study 
Observational studies are increasingly being used to estimate the effect of treatments, interventions and exposures on outcomes that can occur over time. Historically, the hazard ratio, which is a relative measure of effect, has been reported. However, medical decision making is best informed when both relative and absolute measures of effect are reported. When outcomes are time-to-event in nature, the effect of treatment can also be quantified as the change in mean or median survival time due to treatment and the absolute reduction in the probability of the occurrence of an event within a specified duration of follow-up. We describe how three different propensity score methods, propensity score matching, stratification on the propensity score and inverse probability of treatment weighting using the propensity score, can be used to estimate absolute measures of treatment effect on survival outcomes. These methods are all based on estimating marginal survival functions under treatment and lack of treatment. We then conducted an extensive series of Monte Carlo simulations to compare the relative performance of these methods for estimating the absolute effects of treatment on survival outcomes. We found that stratification on the propensity score resulted in the greatest bias. Caliper matching on the propensity score and a method based on earlier work by Cole and Hernán tended to have the best performance for estimating absolute effects of treatment on survival outcomes. When the prevalence of treatment was less extreme, then inverse probability of treatment weighting-based methods tended to perform better than matching-based methods.
doi:10.1177/0962280213519716
PMCID: PMC5051602  PMID: 24463885
propensity score; survival analysis; inverse probability of treatment weighting; Monte Carlo simulations; observational study; time-to-event outcomes
10.  Contour plot assessment of meta-analyses: robust association of statins-use and acute kidney injury risk 
Journal of clinical epidemiology  2015;68(10):1138-1143.
Objectives
Robustness of an existing meta-analysis can justify decisions on whether or not to conduct an additional study addressing the same research question. We illustrate the graphical assessment of the potential impact of an additional study on an existing meta-analysis using published data on statin use and the risk of acute kidney injury.
Study Design and Setting
A previously proposed graphical augmentation approach is used to assess sensitivity of current test- and heterogeneity statistics extracted from existing meta-analysis data. In addition, we extended the graphical augmentation approach to assess potential changes in the pooled effect estimate after updating a current meta-analysis and applied the three graphical contour definitions to data from meta-analyses on statins use and acute kidney injury risk.
Results
In the considered example data, the pooled effect estimates and heterogeneity indices demonstrated to be considerably robust to the addition of a future study. Supportingly, for some previously inconclusive meta-analyses, a study update might yield statistically significant kidney injury risk increase associated with higher statins exposure.
Conclusion
The illustrated contour approach should become a standard tool for the assessment of the robustness of meta-analyses. It can guide decisions on whether to conduct additional studies addressing a relevant research question.
doi:10.1016/j.jclinepi.2015.05.030
PMCID: PMC5035149  PMID: 26092287 CAMSID: cams5959
11.  Targeted Maximum Likelihood Estimation for Pharmacoepidemiologic Research 
Epidemiology (Cambridge, Mass.)  2016;27(4):570-577.
Supplemental Digital Content is available in the text.
Background:
Targeted maximum likelihood estimation has been proposed for estimating marginal causal effects, and is robust to misspecification of either the treatment or outcome model. However, due perhaps to its novelty, targeted maximum likelihood estimation has not been widely used in pharmacoepidemiology. The objective of this study was to demonstrate targeted maximum likelihood estimation in a pharmacoepidemiological study with a high-dimensional covariate space, to incorporate the use of high-dimensional propensity scores into this method, and to compare the results to those of inverse probability weighting.
Methods:
We implemented the targeted maximum likelihood estimation procedure in a single-point exposure study of the use of statins and the 1-year risk of all-cause mortality postmyocardial infarction using data from the UK Clinical Practice Research Datalink. A range of known potential confounders were considered, and empirical covariates were selected using the high-dimensional propensity scores algorithm. We estimated odds ratios using targeted maximum likelihood estimation and inverse probability weighting with a variety of covariate selection strategies.
Results:
Through a real example, we demonstrated the double robustness of targeted maximum likelihood estimation. We showed that results with this method and inverse probability weighting differed when a large number of covariates were included in the treatment model.
Conclusions:
Targeted maximum likelihood can be used in high-dimensional covariate settings. In high-dimensional covariate settings, differences in results between targeted maximum likelihood and inverse probability weighted estimation are likely due to sensitivity to (near) positivity violations. Further investigations are needed to gain better understanding of the advantages and limitations of this method in pharmacoepidemiological studies.
doi:10.1097/EDE.0000000000000487
PMCID: PMC4890840  PMID: 27031037
12.  Effects of analogue insulin in multiple daily injection therapy of type 2 diabetes on postprandial glucose control and cardiac function compared to human insulin: a randomized controlled long-term study 
Background
The prevention of cardiovascular disease, including diastolic cardiac dysfunction with its high prevalence and ominous prognosis, is a therapeutic challenge for patients with type 2 diabetes. Both short and long-acting insulin analogues (AI) have been shown to reduce glucose variability and provide potential benefit for cardiovascular disease although the effects on cardiac function have not yet been evaluated. This long-term, prospective, randomized controlled trial in patients with type 2 diabetes (T2D) tested the hypothesis that a multiple daily injection regimen (MDI) with AI improves postmeal glucose excursions in comparison to human insulin (HI) and that the effects of AI improve diastolic cardiac function.
Methods
For 36 months, MDI treatment in 109 T2D patients was adapted every 3 months (targets: fasting glucose ≤ 110 mg/dl, postmeal glucose ≤ 150 mg/dl) in both groups: AI (insulin detemir and insulin aspart, n = 61) and HI (NPH-insulin and regular HI, n = 48). Diastolic cardiac function (myocardial velocity E’ using tissue Doppler imaging and the mitral inflow ratio E/A) and vascular function were assessed before and 2 h after a standardized breakfast (48 g carbohydrates). At baseline, both groups were comparable with regards to demographic, cardiac and metabolic data. Analysis of data included traditional statistics as well as the use of a multiple imputation technique shown in brackets [ ].
Results
At 36 months, the primary endpoint, postmeal glucose, decreased by 20 ± 62 mg/dl, p = 0.038 [p = 0.021] with AI and increased insignificantly with HI (inter-group p = 0.032 [p = 0.047]) to postmeal glucose levels of 161 ± 39 with AI vs. 195 ± 54 mg/dl with HI (inter-group p = 0.002 [p = 0.010]) whereas the levels of fasting glucose and HbA1c were comparable. With AI, postmeal E’ improved by 0.6 ± 1.4 cm/s, p = 0.009 [p = 0.002] and fasting E’ by 0.4 ± 1.4 cm/s, p = 0.069 [p = 0.013], however, E’ remained unchanged with HI. These changes were consistent with those of the traditional parameter E/A.
Conclusions
MDI with AI results in better postmeal glucose control compared to HI. The treatment with AI is associated with improved diastolic cardiac function.
ClinicalTrials.gov (NTC00747409)
doi:10.1186/s12933-015-0320-2
PMCID: PMC4715313  PMID: 26772807
Analogue insulins; Human insulin; Postprandial glucose; Metabolic control; Diastolic cardiac function; Insulin resistance; Type 2 diabetes; Diastolic dysfunction
13.  Statistical power in parallel group point exposure studies with time-to-event outcomes: an empirical comparison of the performance of randomized controlled trials and the inverse probability of treatment weighting (IPTW) approach 
Background
Estimating statistical power is an important component of the design of both randomized controlled trials (RCTs) and observational studies. Methods for estimating statistical power in RCTs have been well described and can be implemented simply. In observational studies, statistical methods must be used to remove the effects of confounding that can occur due to non-random treatment assignment. Inverse probability of treatment weighting (IPTW) using the propensity score is an attractive method for estimating the effects of treatment using observational data. However, sample size and power calculations have not been adequately described for these methods.
Methods
We used an extensive series of Monte Carlo simulations to compare the statistical power of an IPTW analysis of an observational study with time-to-event outcomes with that of an analysis of a similarly-structured RCT. We examined the impact of four factors on the statistical power function: number of observed events, prevalence of treatment, the marginal hazard ratio, and the strength of the treatment-selection process.
Results
We found that, on average, an IPTW analysis had lower statistical power compared to an analysis of a similarly-structured RCT. The difference in statistical power increased as the magnitude of the treatment-selection model increased.
Conclusions
The statistical power of an IPTW analysis tended to be lower than the statistical power of a similarly-structured RCT.
doi:10.1186/s12874-015-0081-3
PMCID: PMC4608110  PMID: 26472109
Observational study; Propensity score; Inverse probability of treatment weighting; Causal inference; Survival analysis; Randomized controlled trial; Monte Carlo simulations
14.  Human papilloma virus is not detectable in samples of urothelial bladder cancer in a central European population: a prospective translational study 
Background
Previous investigations on the association of human papillomavirus (HPV) and human bladder cancer have led to conflicting results. The aim of this study was to determine if low and high risk HPV play a role in the etiology of superficial low grade and invasive high grade urothelial carcinoma of the bladder.
Methods
We prospectively collected tumor samples of urothelial carcinoma of the bladder from 109 patients treated with transurethral resection or cystectomy, with bladder tissue from transurethral resection of the prostate serving as control. Unfixed, frozen tumor samples were analyzed for the presence of 14 high risk HPV types using real time PCR. Additionally, all specimens were tested for 35 low risk HPV types with a conventional PCR using degenerate primers located in the L1 region. Six frozen samples of cervical carcinoma served as positive controls.
Results
We included 109 cases of bladder cancer with 41 superficial (pTa low grade) tumors, 56 invasive (pT1-T4) high grade tumors and 12 others (pTa high grade + pTis). We have not detected HPV-DNA in any sample (95 % Confidence Interval [CI] 0–3.3 %), superficial tumors (95 % CI 0–6.4 %) or in invasive tumors (95 % CI 0–8.6 %) with correct positive controls.
Conclusions
Using a broad, sensitive assay with prospectively collected specimens of a Central European population we could not detect HPV-DNA in any of the cases. Our results suggest that it is unlikely that HPV infections play a major role in the development of urothelial bladder cancer.
doi:10.1186/s13027-015-0028-7
PMCID: PMC4576373  PMID: 26392819
Bladder cancer; Urothelial carcinoma; Papillomavirus; HPV; PCR; Polymerase chain reaction
15.  Predictors of the accuracy of pulse-contour cardiac index and suggestion of a calibration-index: a prospective evaluation and validation study 
BMC Anesthesiology  2015;15:45.
Background
Cardiac Index (CI) is a key-parameter of hemodynamic monitoring. Indicator-dilution is considered as gold standard and can be obtained by pulmonary arterial catheter or transpulmonary thermodilution (TPTD; CItd). Furthermore, CI can be estimated by Pulse-Contour-Analysis (PCA) using arterial wave-form analysis (CIpc). Obviously, adjustment of CIpc to CItd initially improves the accuracy of CIpc. Despite uncertainty after which time accuracy of CIpc might be inappropriate, recalibration by TPTD is suggested after a maximum of 8 h.
We hypothesized that accuracy of CIpc might not only depend on time to last TPTD, but also on changes of the arterial wave curve detectable by PCA itself. Therefore, we tried to prospectively characterize predictors of accuracy and precision of CIpc (primary outcome). In addition to “time to last TPTD” we evaluated potential predictors detectable solely by pulse-contour-analysis.
Finally, the study aimed to develop a pulse-contour-derived “calibration-index” suggesting recalibration and to validate these results in an independent collective.
Methods
In 28 intensive-care-patients with PiCCO-monitoring (Pulsion Medical-Systems, Germany) 56 datasets were recorded. CIpc-values at baseline and after intervals of 1 h, 2 h, 4 h, 6 h and 8 h were compared to CItd derived from immediately subsequent TPTD. Results from this evaluation-collective were validated in an independent validation-collective (49 patients, 67 datasets).
Results
Mean bias values CItd-CIpc after different intervals ranged between -0.248 and 0.112 L/min/m2. Percentage-error after different intervals to last TPTD ranged between 18.6% (evaluation, 2 h-interval) and 40.3% (validation, 6 h-interval). In the merged data, percentage-error was below 30% after 1 h, 2 h, 4 h and 8 h, and exceeded 30% only after 6 h. “Time to last calibration” was neither associated to accuracy nor to precision of CIpc in any uni- or multivariate analysis.
By contrast, the height of CIpc and particularly changes in CIpc compared to last thermodilution-derived CItd(base) univariately and independently predicted the bias CItd-CIpc in both collectives.
Relative changes of CIpc compared to CItd(base) exceeding thresholds derived from the evaluation-collective (-11.6% < CIpc-CItd(base)/CItd(base) < 7.4%) were confirmed as significant predictors of a bias |CItd-CIpc| ≥ 20% in the validation-collective.
Conclusion
Recalibration triggered by changes of CIpc compared to CItd(base) derived from last calibration should be preferred to fixed intervals.
doi:10.1186/s12871-015-0024-x
PMCID: PMC4389926  PMID: 25861243
Hemodynamic monitoring; Pulse contour analysis; Cardiac output; Cardiac index; Calibration; Transpulmonary thermodilution; Accuracy; Precision
16.  The CORE study protocol: a stepped wedge cluster randomised controlled trial to test a co-design technique to optimise psychosocial recovery outcomes for people affected by mental illness in the community mental health setting 
BMJ Open  2015;5(3):e006688.
Introduction
User engagement in mental health service design is heralded as integral to health systems quality and performance, but does engagement improve health outcomes? This article describes the CORE study protocol, a novel stepped wedge cluster randomised controlled trial (SWCRCT) to improve psychosocial recovery outcomes for people with severe mental illness.
Methods
An SWCRCT with a nested process evaluation will be conducted over nearly 4 years in Victoria, Australia. 11 teams from four mental health service providers will be randomly allocated to one of three dates 9 months apart to start the intervention. The intervention, a modified version of Mental Health Experience Co-Design (MH ECO), will be delivered to 30 service users, 30 carers and 10 staff in each cluster. Outcome data will be collected at baseline (6 months) and at completion of each intervention wave. The primary outcome is improvement in recovery score using the 24-item Revised Recovery Assessment Scale for service users. Secondary outcomes are improvements to user and carer mental health and well-being using the shortened 8-item version of the WHOQOL Quality of Life scale (EUROHIS), changes to staff attitudes using the 19-item Staff Attitudes to Recovery Scale and recovery orientation of services using the 36-item Recovery Self Assessment Scale (provider version). Intervention and usual care periods will be compared using a linear mixed effects model for continuous outcomes and a generalised linear mixed effects model for binary outcomes. Participants will be analysed in the group that the cluster was assigned to at each time point.
Ethics and dissemination
The University of Melbourne, Human Research Ethics Committee (1340299.3) and the Federal and State Departments of Health Committees (Project 20/2014) granted ethics approval. Baseline data results will be reported in 2015 and outcomes data in 2017.
Trial registration number
Australian and New Zealand Clinical Trials Registry ACTRN12614000457640.
doi:10.1136/bmjopen-2014-006688
PMCID: PMC4386225  PMID: 25805530
PRIMARY CARE; PSYCHIATRY
17.  Association between Different Indexations of Extravascular Lung Water (EVLW) and PaO2/FiO2: A Two-Center Study in 231 Patients 
PLoS ONE  2014;9(8):e103854.
Background
Variability of body weight (BW) and height calls for indexation of volumetric hemodynamic parameters. Extravascular lung water (EVLW) has formerly been indexed to actual BW (BWact) termed EVLW-index (EVLWI). In overweight patients indexation to BWact might inappropriately lower indexed EVLWIact. Several studies suggest indexation of EVLWI to predicted BW (EVLWIpred). However, data regarding association of EVLWIact and EVLWpred to mortality and PaO2/FiO2 are inconsistent. Two recent studies based on biometric database-analyses suggest indexation of EVLWI to height (EVLWIheight). Therefore, our study compared the association of un-indexed EVLW, EVLWIheight, EVLWpred and EVLWIact to PaO2/FiO2 and Oxygenation index (OI = mean airway pressure*FiO2*/PaO2).
Methods
A total of 2119 triplicate transpulmonary thermodilutions (TPTDs; PiCCO; Pulsion Medical-Systems, Germany) were performed in 50 patients from the evaluation, and 181 patients from the validation groups. Correlations of EVLW and EVLWI to PaO2/FiO2, OI and ROC-AUC-analyses regarding PaO2/FiO2<200 mmHg (primary endpoint) and OI>10 were performed.
Results
In the evaluation group, un-indexed EVLW (AUC 0.758; 95%-CI: 0.637-0.880) and EVLWIheight (AUC 0.746; 95%-CI: 0.622-0.869) provided the largest ROC-AUCs regarding PaO2/FiO2<200 mmHg. The AUC for EVLWIpred was smaller (0.713). EVLWIact provided the smallest AUC (0.685). This was confirmed in the validation group: EVLWIheight provided the largest AUC (0.735), EVLWIact (0.710) the smallest. In the merged data-pool, AUC was significantly greater for EVLWIheight (0.729; 95%-CI: 0.674–0.784) compared to all other indexations including EVLWIact (ROC-AUC 0.683, p = 0.007) and EVLWIpred (ROC-AUC 0.707, p = 0.015). The association of EVLW(I) was even stronger to OI compared to PaO2/FiO2. In the merged data-pool, EVLWIheight provided the largest AUC regarding “OI>10” (0.778; 95%-CI: 0.713–0.842) compared to 0.739 (95%-CI: 0.669–0.810) for EVLWIact and 0.756 (95%-CI: 0.688–0.824) for EVLWIpred.
Conclusions
Indexation of EVLW to height (EVLWIheight) improves the association of EVLW(I) to PaO2/FiO2 and OI compared to all other indexations including EVLWIpred and EVLWIact. Also considering two recent biometric database analyses, EVLWI should be indexed to height.
doi:10.1371/journal.pone.0103854
PMCID: PMC4122373  PMID: 25093821
18.  Chronic stress and coping among cardiac surgeons: a single center study 
Introduction
Cardiac surgeons stress may impair their quality of life and professional practice.
Objective
To assess perceived chronic stress and coping strategies among cardiac surgeons.
Methods
Twenty-two cardiac surgeons answered two self-assessment questionnaires, the Trier Inventory for Chronic Stress and the German SGV for coping strategies.
Results
Participants mean age was 40±14.1 years and 13 were male; eight were senior physicians and 14 were residents. Mean values for the Trier Inventory for Chronic Stress were within the normal range. Unexperienced physicians had significantly higher levels of dissatisfaction at work, lack of social recognition, and isolation (P<0.05). Coping strategies such as play down, distraction from situation, and substitutional satisfaction were also significantly more frequent among unexperienced surgeons. "Negative" stress-coping strategies occur more often in experienced than in younger colleagues (P=0.029). Female surgeons felt more exposed to overwork (P=0.04) and social stress (P=0.03).
Conclusion
Cardiac surgeons show a tendency to high perception of chronic stress phenomena and vulnerability for negative coping strategies.
doi:10.5935/1678-9741.20140083
PMCID: PMC4412318  PMID: 25372902
Stress, Psychological; Cardiac Surgical Procedures; Case Studies
19.  Week one FLT-PET response predicts complete remission to R-CHOP and survival in DLBCL 
Oncotarget  2014;5(12):4050-4059.
Despite improved survival in the Rituximab (R) era, a considerable number of patients with diffuse large B-cell lymphoma (DLBCL) ultimately die from the disease. Functional imaging using [18F]fluorodeoxyglucose-PET is suggested for assessment of residual viable tumor very early during treatment but is compromised by non-specific tracer retention in inflammatory lesions. The PET tracer [18F]fluorodeoxythymidine (FLT) as surrogate marker of tumor proliferation may overcome this limitation. We present results of a prospective clinical study testing FLT-PET as superior and early predictor of response to chemotherapy and outcome in DLBCL. 54 patients underwent FLT-PET prior to and one week after the start of R-CHOP chemotherapy. Repetitive FLT-PET imaging was readily implemented into the diagnostic work-up. Our data demonstrate that the reduction of FLT standard uptake valuemean (SUVmean) and SUVmax one week after chemotherapy was significantly higher in patients achieving complete response (CR, n=48; non-CR, n=6; p<0.006). Martingale-residual and Cox proportional hazard analyses showed a significant monotonous decrease of mortality risk with increasing change in SUV. Consistent with these results, early FLT-PET response showed relevant discriminative ability in predicting CR. In conclusion, very early FLT-PET in the course of R-CHOP chemotherapy is feasible and enables identification of patients at risk for treatment failure.
PMCID: PMC4147305  PMID: 24979177
Lymphoma; DLBCL; Positron emission tomography; [18F]Fluorodeoxythymidine; FLT-PET
20.  Validation of In Vivo MRI Blood-Brain Barrier Permeability Measurements by Comparison with Gold Standard Histology 
Background and Purpose
To validate the blood-brain barrier permeability measurements extracted from perfusion-weighted MRI through a relatively simple and frequently applied model, the Patlak model, by comparison with gold standard histology in a rat model of ischemic stroke.
Methods
Eleven spontaneously hypertensive rats and eleven Wistar rats with unilateral, 2h filament occlusion of the right MCA underwent imaging during occlusion, at 4h and 24h post reperfusion. BBB permeability was imaged by gradient echo imaging after the first pass of the contrast agent bolus and quantified by a Patlak analysis. BBB permeability was shown on histology by the extravasation of Evans blue on fluorescence microscopy sections matching location and orientation of MR images. Cresyl-violet staining was used to detect and characterize hemorrhage. Landmark-based elastic image registration allowed a region-by-region comparison of permeability imaging at 24 hours with Evans blue extravasation and hemorrhage as detected on histological slides obtained immediately after the 24-hour image set.
Results
Permeability values in the non-ischemic tissue (marginal mean±SE: 0.15±0.019ml/min·100ml) were significantly lower compared to all permeability values in regions of Evans blue extravasation or hemorrhage. Permeability values in regions of weak Evans blue extravasation (0.23±0.016ml/min·100ml) were significantly lower compared to permeability values of in regions of strong Evans blue extravasation (0.29±0.020ml/min·100ml) and macroscopic hemorrhage (0.35±0.049ml/min·100ml). Permeability values in regions of microscopic hemorrhage (0.26±0.024ml/min·100ml) only differed significantly from values in regions of non-ischemic tissue (0.15±0.019 ml/min·100ml).
Conclusion
Areas of increased permeability measured in-vivo by imaging coincide with BBB disruption and hemorrhage observed on gold standard histology.
doi:10.1161/STROKEAHA.110.597997
PMCID: PMC3921072  PMID: 21636816
ischemic stroke; hemorrhagic transformation; blood-brain barrier permeability; MRI; validation study
21.  Endosonography For Right-sided and Acute Upper Intestinal Misery: the EFRAIM study 
Background
Acute upper abdominal pain is a frequent symptom leading to hospital admission.
Objective
To determine whether a primary intra- and extraluminal diagnostic approach enabled by endoscopic ultrasound is as effective as a conventional diagnostic algorithm of transabdominal ultrasound followed by oesophagogastroduodenoscopy.
Methods
A total of 240 patients who presented with acute right-sided and/or upper abdominal pain were prospectively recruited. Exclusion criteria were chronic pain, malignancy, prior abdominal surgery, bleeding, peritonitis, and elevated liver enzymes or lipase as defined 3-times higher than upper reference value. All patients underwent first transabdominal ultrasound and were then randomized (1 : 1) to either endoscopy followed by endoscopic ultrasound or vice versa. Patients and respective examiners were blinded to prior findings.
Results
A total of 223 patients were included. Endoscopic ultrasound provided a higher diagnostic yield than the combination of transabdominal ultrasound and endoscopy (62.3 vs. 50.7%; p = 0.001). For mucosal/intraluminal lesions, we observed a very good agreement between both endoscopic modalities (kappa 0.89). The agreement for pancreatic and biliary causes was good between both ultrasound modalities (kappa 0.66).
Conclusions
Due to its high diagnostic yield, endoscopic ultrasound as a primary diagnostic modality appears to be a valuable option in patients with acute upper abdominal pain.
doi:10.1177/2050640613498589
PMCID: PMC4040764  PMID: 24917980
Biliary; endoscopy; EUS; gastrointestinal; pain
22.  Safety and efficacy of a lifestyle intervention for pregnant women to prevent excessive maternal weight gain: a cluster-randomized controlled trial 
Background
Excessive gestational weight gain (GWG) is associated with short- and long-term health problems among mothers and their offspring. There is a strong need for effective intervention strategies targeting excessive GWG to prevent adverse outcomes.
Methods
We performed a cluster-randomized controlled intervention trial in eight gynecological practices evaluating the feasibility and effectiveness of a lifestyle intervention presented to all pregnant women; 250 healthy, pregnant women were recruited for the study. The intervention program consisted of two individually delivered counseling sessions focusing on diet, physical activity, and weight monitoring. The primary outcome was the proportion of pregnant women exceeding weight gain recommendations of the Institute of Medicine (IOM). Secondary outcome variables were maternal weight retention and short-term obstetric and neonatal outcomes.
Results
The intervention resulted in a lower proportion of women exceeding IOM guidelines among women in the intervention group (38%) compared with the control group (60%) (odds ratio (OR): 0.5; 95% confidence interval (CI): 0.3 to 0.9) without prompting an increase in the proportion of pregnancies with suboptimal weight gain (19% vs. 21%). Participants in the intervention group gained significantly less weight than those in the control group. Only 17% of the women in the intervention group showed substantial weight retention of more than 5 kg compared with 31% of those in the control group at month four postpartum (pp) (OR: 0.5; 95% CI: 0.2 to 0.9). There were no significant differences in obstetric and neonatal outcomes.
Conclusions
Lifestyle counseling given to pregnant women reduced the proportion of pregnancies with excessive GWG without increasing suboptimal weight gain, and may exert favorable effects on pp weight retention.
Trial registration
German Clinical Trials Register DRKS00003801.
doi:10.1186/1471-2393-13-151
PMCID: PMC3718707  PMID: 23865624
Gestational weight gain (GWG); Lifestyle intervention; Pregnancy; Obesity prevention and management; Feasibility study
23.  Evaluation of the Hepa Wash® treatment in pigs with acute liver failure 
BMC Gastroenterology  2013;13:83.
Background
Mortality of patients with acute liver failure (ALF) is still unacceptably high. Available liver support systems are still of limited success at improving survival. A new type of albumin dialysis, the Hepa Wash® system, was newly introduced. We evaluated the new liver support system as well as the Molecular Adsorbent Recycling System (MARS) in an ischemic porcine model of ALF.
Methods
In the first study animals were randomly allocated to control (n=5) and Hepa Wash (n=6) groups. In a further pilot study, two animals were treated with the MARS-system. All animals received the same medical and surgical procedures. An intraparenchymal intracranial pressure was inserted. Hemodynamic monitoring and goal-directed fluid therapy using the PiCCO system was done. Animals underwent functional end-to-side portacaval shunt and ligation of hepatic arteries. Treatment with albumin dialysis was started after fall of cerebral perfusion pressure to 45 mmHg and continued for 8 h.
Results
All animals in the Hepa Wash group survived the 13-hour observation period, except for one that died after stopping treatment. Four of the control animals died within this period (p=0.03). Hepa Wash significantly reduced impairment of cerebral perfusion pressure (23±2 vs. 10±3 mmHg, p=0.006) and mean arterial pressure (37±1 vs. 24±2 mmHg, p=0.006) but had no effect on intracranial pressure (14±1 vs. 15±1 mmHg, p=0.72). Hepa Wash also enhanced cardiac index (4.94±0.32 vs. 3.36±0.25 l/min/m2, p=0.006) and renal function (urine production, 1850 ± 570 vs. 420 ± 180 ml, p=0.045) and eliminated water soluble (creatinine, 1.3±0.2 vs. 3.2±0.3 mg/dl, p=0.01; ammonia 562±124 vs. 1382±92 μg/dl, p=0.006) and protein-bound toxins (nitrate/nitrite 5.54±1.57 vs. 49.82±13.27 μmol/l, p=0.01). No adverse events that could be attributed to the Hepa Wash treatment were observed.
Conclusions
Hepa Wash was a safe procedure and improved multiorgan system failure in pigs with ALF. The survival benefit could be the result of ameliorating different organ functions in association with the detoxification capacity of water soluble and protein-bound toxins.
doi:10.1186/1471-230X-13-83
PMCID: PMC3659067  PMID: 23668774
Artificial liver; Acute liver failure; Albumin dialysis; Animal model; Swine; Renal dialysis; Multiple organ failure; Capillary leak syndrome; Cardiovascular failure; Renal failure
24.  Downregulation of Serine Protease HTRA1 Is Associated with Poor Survival in Breast Cancer 
PLoS ONE  2013;8(4):e60359.
HTRA1 is a highly conserved serine protease which has been implicated in suppression of epithelial-to-mesenchymal-transition (EMT) and cell motility in breast cancer. Its prognostic relevance for breast cancer is unclear so far. Therefore, we evaluated the impact of HTRA1 mRNA expression on patient outcome using a cohort of 131 breast cancer patients as well as a validation cohort including 2809 publically available data sets. Additionally, we aimed at investigating for the presence of promoter hypermethylation as a mechanism for silencing the HTRA1 gene in breast tumors. HTRA1 downregulation was detected in more than 50% of the breast cancer specimens and was associated with higher tumor stage (p = 0.025). By applying Cox proportional hazard models, we observed favorable overall (OS) and disease-free survival (DFS) related to high HTRA1 expression (HR = 0.45 [CI 0.23–0.90], p = 0.023; HR = 0.55 [CI 0.32–0.94], p = 0.028, respectively), with even more pronounced impact in node-positive patients (HR = 0.21 [CI 0.07–0.63], p = 0.006; HR = 0.29 [CI 0.13–0.65], p = 0.002, respectively). Moreover, HTRA1 remained a statistically significant factor predicting DFS among established clinical parameters in the multivariable analysis. Its impact on patient outcome was independently confirmed in the validation set (for relapse-free survival (n = 2809): HR = 0.79 [CI 0.7–0.9], log-rank p = 0.0003; for OS (n = 971): HR = 0.63 [CI 0.48–0.83], log-rank p = 0.0009). In promoter analyses, we in fact detected methylation of HTRA1 in a small subset of breast cancer specimens (two out of a series of 12), and in MCF-7 breast cancer cells which exhibited 22-fold lower HTRA1 mRNA expression levels compared to unmethylated MDA-MB-231 cells. In conclusion, we show that downregulation of HTRA1 is associated with shorter patient survival, particularly in node-positive breast cancer. Since HTRA1 loss was demonstrated to induce EMT and cancer cell invasion, these patients might benefit from demethylating agents or histone deacetylase inhibitors previously reported to lead to HTRA1 upregulation, or from novel small-molecule inhibitors targeting EMT-related processes.
doi:10.1371/journal.pone.0060359
PMCID: PMC3620283  PMID: 23580433
25.  Acupuncture compared to oral antihistamine for type I hypersensitivity itch and skin response in adults with atopic dermatitis – a patient and examiner blinded, randomized, placebo-controlled, crossover trial 
Allergy  2012;67(4):566-573.
Background
Itch is the major symptom of atopic dermatitis (AD). Acupuncture has been shown to exhibit a significant effect on experimental itch in AD. Our study evaluated acupuncture and anti-histamine itch therapy (cetirizine) on type-I-hypersensitivity itch and skin reaction in AD using a patient and examiner blinded, randomized, placebo-controlled, crossover trial.
Methods
Allergen–induced itch was evaluated in 20 AD patients after several interventions in separate sessions: preventive (preceding) and abortive (concurrent) verum acupuncture (VAp and VAa), cetirizine (10mg, VC), corresponding placebo interventions (preventive, PAp, and abortive, PAa, placebo acupuncture; placebo cetirizine pill, PC), and a no-intervention control (NI). Itch was induced on the forearm and temperature modulated over 20 minutes, using our validated model. Outcome parameters included itch intensity, wheal and flare size, and the D2 Attention test.
Results
Mean itch intensity (SE: 0.31 each) was significantly lower following VAa (31.9) compared to all other groups (PAa: 36.5; VC: 36.8; VAp: 37.6; PC: 39.8; PAp: 39.9; NI: 45.7, p<0.05). There was no significant difference between VAp and VC (p>0.1), though both therapies were significantly superior to their respective placebo interventions (p<0.05). Flare size following VAp was significantly smaller (p=0.034) than PAp. D2 attention test score was significantly lower following VC compared to all other groups (p<0.001).
Conclusions
Both VA and cetirizine significantly reduced type-I-hypersensitivity itch in AD patients, compared to both placebo and NI. Timing of acupuncture application was important, as VAa had the most significant effect on itch, potentially due to counter-irritation and/or distraction. Itch reduction following cetirizine coincided with reduced attention.
doi:10.1111/j.1398-9995.2012.02789.x
PMCID: PMC3303983  PMID: 22313287
Itch; allergen; acupuncture; atopic eczema; cetirizine; attention

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