Summary
Introduction
Standardization of BCR‐ABL1 messenger RNA quantification by real‐time PCR on the International Scale (IS) is critical for monitoring therapy response in chronic myelogenous ...leukaemia. Since 2006, BCR‐ABL1 IS standardization is propagated along reference laboratories by calculating a laboratory‐specific conversion factor (CF), co‐ordinated in Europe through the European Treatment and Outcome Study project. Although this process has proven successful to some extent, it has not been achievable for all laboratories due to the complexity of the process and the stringent requirements in terms of numbers of samples to be exchanged. In addition, several BCR‐ABL1 IS quantification methods and secondary reference materials became commercially available. However, it was observed that different IS methods generate consistently different results.
Methods
To overcome these difficulties, we have developed an alternative and simple approach of CF calculation, based on the retrospective analysis of existing external quality assessment (EQA) data. Our approach does not depend on the exchange of samples and is solely based on the mathematical CF calculation using EQA results.
Results and conclusion
We have demonstrated by thorough statistical validation that this approach performs well in converting BCR‐ABL1 measurements to improve IS estimation. In expectation of a true golden standard method for BCR‐ABL1 IS quantification, the proposed method is a valuable alternative.
Existing pencil beam analytical (PBA) algorithms for proton therapy treatment planning are not ideal for sites with heterogeneous tissue density and do not account for the spatial variations in ...proton relative biological effectiveness (vRBE). Using a commercially available Monte Carlo (MC) treatment planning system, we compared various dosimetric endpoints between proton PBA, proton MC, and photon treatment plans among patients with mediastinal lymphoma.
Eight mediastinal lymphoma patients with both free breathing (FB) and deep inspiration breath hold (DIBH) CT simulation scans were analyzed. The original PBA plans were re-calculated with MC. New proton plans that used MC for both optimization and dose calculation with equivalent CTV/ITV coverage were also created. A vRBE model, which uses a published model for DNA double strand break (DSB) induction, was applied on MC plans to study the potential impact of vRBE on cardiac doses. Comparative photon plans were generated on the DIBH scan.
Re-calculation of FB PBA plans with MC demonstrated significant under coverage of the ITV V99 and V95. Target coverage was recovered by re-optimizing the PT plan with MC with minimal change to OAR doses. Compared to photons with DIBH, MC-optimized FB and DIBH proton plans had significantly lower dose to the mean lung, lung V5, breast tissue, and spinal cord for similar target coverage. Even with application of vRBE in the proton plans, the putative increase in RBE at the end of range did not decrease the dosimetric advantages of proton therapy in cardiac substructures.
MC should be used for PT treatment planning of mediastinal lymphoma to ensure adequate coverage of target volumes. Our preliminary data suggests that MC-optimized PT plans have better sparing of the lung and breast tissue compared to photons. Also, the potential for end of range RBE effects are unlikely to be large enough to offset the dosimetric advantages of proton therapy in cardiac substructures for mediastinal targets, although these dosimetric findings require validation with late toxicity data.
Context:
Gonadectomy is avoided whenever possible in boys with 45,X/46,XY. However, no clinical markers are currently available to guide clinicians in predicting gonadal tumor risk or hormone ...production.
Objective:
The objective of the study was to test the hypothesis that gonadal histology and risk for development of a malignant germ cell tumor are reflected by the clinical presentation of a 45,X/46,XY individual.
Design:
The design of the study was the correlation of clinical data external masculinization score (EMS), pubertal outcome with pathology data (gonadal phenotype, tumor risk).
Setting:
This was a multicenter study involving two multidisciplinary disorder of sex development teams.
Patients:
Patients included genetically proven 45,X/46,XY (and variants) cases, of whom at least one gonadal biopsy or gonadectomy specimen was available, together with clinical details.
Interventions:
Patients (n = 48) were divided into three groups, based on the EMS. Gonadal histology and tumor risk were assessed on paraffin-embedded samples (n = 87) by morphology and immunohistochemistry on the basis of established criteria.
Main Outcome Measures:
Gonadal differentiation and tumor risk in the three clinical groups were measured. Clinical outcome in patients with at least one preserved gonad was also measured.
Results:
Tumor risk in the three groups was significantly related to the gonadal differentiation pattern (P < 0.001). In boys, hormone production was sufficient and was not predicted by the EMS.
Conclusions:
The EMS reflects gonadal differentiation and tumor risk in patients with 45,X/46,XY. In boys, testosterone production is often sufficient, but strict follow-up is warranted because of malignancy risk, which appears inversely related to EMS. In girls, tumor risk is limited but gonads are not functional, making gonadectomy the most reasonable option.
Background
This study was performed to assess adhesion molecules in systemic lupus erythematosus (SLE).
Methods
This case-control study examined 126 SLE patients and 48 healthy individuals. Blood ...levels of six adhesion molecules, cortisol, nuclear autoantibody (ANA) and anti-double stranded DNA (anti-dsDNA) titers were measured, while disease activity was assessed using the SLE Disease Activity Index (SLEDAI) score.
Results
Platelet endothelial cell adhesion molecule 1 (PECAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, P-selectin, and plasminogen activator inhibitor type-1 (PAI-1) were significantly higher in SLE patients than in controls. Binary logistic regression analysis showed that PECAM-1 and PAI-1 predicted SLE with a sensitivity of 86.5% and a specificity of 81.3%. ANA titers were significantly and positively associated with PECAM-1, VCAM-1, E-selectin, and PAI-1, whereas there were no associations between anti-dsDNA titers and adhesion molecules. Cortisol was negatively associated with PCAM-1 and ICAM-1. There were significant associations between metabolic syndrome (MetS) and E-selectin and PAI-1. 14.8% of the variance in the SLEDAI score was explained by the regression on PECAM-1 and MetS.
Conclusions
Our data show that adhesion molecules, especially PECAM-1, are significantly associated with SLE and disease activity, suggesting that they play a role in SLE pathophysiology. While MetS, ANA titers and cortisol levels modulate adhesion molecule levels, these associations do not explain the increased levels of adhesion molecules in SLE. Increased levels of adhesion molecules are new drug targets in SLE.
Certain bloodsucking insects deliver nitric oxide (NO) while feeding, to induce vasodilation and inhibit blood coagulation. We have expressed, characterized, and determined the crystal structure of ...the Cimex lectularius (bedbug) nitrophorin, the protein responsible for NO storage and delivery, to understand how the insect successfully handles this reactive molecule. Surprisingly, NO binds not only to the ferric nitrophorin heme, but it can also be stored as an S-nitroso (SNO) conjugate of the proximal heme cysteine (Cys-60) when present at higher concentrations. EPR- and UV-visible spectroscopies, and a crystallographic structure determination to 1.75-Å resolution, reveal SNO formation to proceed with reduction of the heme iron, yielding an Fe-NO complex. Stopped-flow kinetic measurements indicate that an ordered reaction mechanism takes place: initial NO binding occurs at the ferric heme and is followed by heme reduction, Cys-60 release from the heme iron, and SNO formation. Release of NO occurs through a reversal of these steps. These data provide, to our knowledge, the first view of reversible metal-assisted SNO formation in a protein and suggest a mechanism for its role in NO release from ferrous heme. This mechanism and Cimex nitrophorin structure are completely unlike those of the nitrophorins from Rhodnius prolixus, where NO protection is provided by a large conformational change that buries the heme nitrosyl complex, highlighting the remarkable evolution of proteins that assist insects in bloodfeeding.
Progressive resistance exercise training (PRET) reduces cardiovascular risk factors (CVRF) in the general population. It is unknown if PRET also reduces these risk factors in adults with intellectual ...disabilities (ID). The aim is to present the protocol of an intervention study that investigates the effect of PRET on CVRF in adults with ID. We will use a repeated time series design with one study group. Adults with mild-to-moderate ID and at least two CVRF are eligible (Netherlands Trial Register, NL8382). During a 12-week baseline period, measurements take place at a 6-week interval. After this, the PRET programme starts for 24 weeks, after which all measurements will be repeated. We will use hierarchical regression models, adjusted for sport activity and medication use, to estimate the effect of PRET. After the intervention, the participants will be followed-up for 12 weeks. We will evaluate factors for successful implementation of exercise in daily life. Primary outcomes are: hypertension, obesity, hypercholesterolemia, diabetes, metabolic syndrome. Secondary outcomes are: physical fitness, sarcopenia, physical activity, activities of daily living, falls, challenging behaviour. If our results show that the PRET programme is effective, it may be a promising non-pharmacological intervention to reduce CVRF in adults with ID.
Twin studies yield valuable insights into the sources of variation, covariation and causation in human traits. The ABCD Study® (abcdstudy.org) was designed to take advantage of four universities ...known for their twin research, neuroimaging, population-based sampling, and expertise in genetic epidemiology so that representative twin studies could be performed. In this paper we use the twin data to: (i) provide initial estimates of heritability for the wide range of phenotypes assessed in the ABCD Study using a consistent direct variance estimation approach, assuring that both data and methodology are sound; and (ii) provide an online resource for researchers that can serve as a reference point for future behavior genetic studies of this publicly available dataset. Data were analyzed from 772 pairs of twins aged 9–10 years at study inception, with zygosity determined using genotypic data, recruited and assessed at four twin hub sites. The online tool provides twin correlations and both standardized and unstandardized estimates of additive genetic, and environmental variation for 14,500 continuously distributed phenotypic features, including: structural and functional neuroimaging, neurocognition, personality, psychopathology, substance use propensity, physical, and environmental trait variables. The estimates were obtained using an unconstrained variance approach, so they can be incorporated directly into meta-analyses without upwardly biasing aggregate estimates. The results indicated broad consistency with prior literature where available and provided novel estimates for phenotypes without prior twin studies or those assessed at different ages. Effects of site, self-identified race/ethnicity, age and sex were statistically controlled. Results from genetic modeling of all 53,172 continuous variables, including 38,672 functional MRI variables, will be accessible via the user-friendly open-access web interface we have established, and will be updated as new data are released from the ABCD Study. This paper provides an overview of the initial results from the twin study embedded within the ABCD Study, an introduction to the primary research domains in the ABCD study and twin methodology, and an evaluation of the initial findings with a focus on data quality and suitability for future behavior genetic studies using the ABCD dataset. The broad introductory material is provided in recognition of the multidisciplinary appeal of the ABCD Study. While this paper focuses on univariate analyses, we emphasize the opportunities for multivariate, developmental and causal analyses, as well as those evaluating heterogeneity by key moderators such as sex, demographic factors and genetic background.
IntroductionThe Healthy Ageing and Intellectual Disability (HA-ID) study is a prospective multicentre cohort study in the Netherlands that started in 2008, including 1050 older adults (aged ≥50) with ...intellectual disabilities (ID). The study is designed to learn more about the health and health risks of this group as they age. Compared with the amount of research in the general population, epidemiological research into the health of older adults with ID is still in its infancy. Longitudinal data about the health of this vulnerable and relatively unhealthy group are needed so that policy and care can be prioritised and for guiding clinical decision making about screening, prevention and treatment to improve healthy ageing.Methods and analysisThis article presents a summary of the previous findings of the HA-ID study and describes the design of the 10-year follow-up in which a wide range of health data will be collected within five research themes: (1) cardiovascular disease; (2) physical activity, fitness and musculoskeletal disorders; (3) psychological problems and psychiatric disorders; (4) nutrition and nutritional state; and (5) frailty.Ethics and disseminationEthical approval for the 10-year follow-up measurements of the HA-ID study has been obtained from the Medical Ethics Review Committee of the Erasmus MC, University Medical Centre Rotterdam (MEC-2019-0562).Trial registration numberThis cohort study is registered in the Dutch Trial Register (NTR number NL8564) and has been conducted according to the principles of the Declaration of Helsinki.
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