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Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3
(2019)
The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation-not only in adult-but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.
Background: Stereotactic radiosurgery (SRS) is an effective treatment for trigeminal neuralgia (TN). Nevertheless, a proportion of patients will experience recurrence and treatment-related sensory disturbances. In order to evaluate the predictors of efficacy and safety of image-guided non-isocentric radiosurgery, we analyzed the impact of trigeminal nerve volume and the nerve dose/volume relationship, together with relevant clinical characteristics.
Methods: Two-hundred and ninety-six procedures were performed on 262 patients at three centers. In 17 patients the TN was secondary to multiple sclerosis (MS). Trigeminal pain and sensory disturbances were classified according to the Barrow Neurological Institute (BNI) scale. Pain-free-intervals were investigated using Kaplan Meier analyses. Univariate and multivariate Cox regression analyses were performed to identify predictors.
Results: The median follow-up period was 38 months, median maximal dose 72.4 Gy, median target nerve volume 25mm3, and median prescription dose 60 Gy. Pain control rate (BNI I-III) at 6, 12, 24, 36, 48, and 60 months were 96.8, 90.9, 84.2, 81.4, 74.2, and 71.2%, respectively. Overall, 18% of patients developed sensory disturbances. Patients with volume ≥ 30mm3 were more likely to maintain pain relief (p = 0.031), and low integral dose (< 1.4 mJ) tended to be associated with more pain recurrence than intermediate (1.4–2.7 mJ) or high integral dose (> 2.7 mJ; low vs. intermediate: log-rank test, χ2 = 5.02, p = 0.019; low vs. high: log-rank test, χ2 = 6.026, p = 0.014). MS, integral dose, and mean dose were the factors associated with pain recurrence, while re-irradiation and MS were predictors for sensory disturbance in the multivariate analysis.
Conclusions: The dose to nerve volume ratio is predictive of pain recurrence in TN, and re-irradiation has a major impact on the development of sensory disturbances after non-isocentric SRS. Interestingly, the integral dose may differ significantly in treatments using apparently similar dose and volume constraints.
Background:
Promoting patient and occupational safety are two key challenges for hospitals. When aiming to improve these two outcomes synergistically, psychosocial working conditions, leadership by hospital management and supervisors, and perceptions of patient and occupational safety climate have to be considered. Recent studies have shown that these key topics are interrelated and form a critical foundation for promoting patient and occupational safety in hospitals. So far, these topics have mainly been studied independently from each other. The present study investigated hospital staffs’ perceptions of four different topics: (1) psychosocial working conditions, (2) leadership, (3) patient safety climate, and (4) occupational safety climate. We present results from a survey in two German university hospitals aiming to detect differences between nurses and physicians.
Methods:
We performed a cross-sectional study using a standardized paper-based questionnaire. The survey was conducted with nurses and physicians to assess the four topics. The instruments mainly consisted of scales of the German version of the COPSOQ (Copenhagen Psychosocial Questionnaire), one scale of the Copenhagen Burnout Inventory (CBI), scales to assess leadership and transformational leadership, scales to assess patient safety climate using the Hospital Survey on Patient Safety Culture (HSPSC), and analogous items to assess occupational safety climate.
Results:
A total of 995 completed questionnaires out of 2512 distributed questionnaires were returned anonymously. The overall response rate was 39.6%. The sample consisted of 381 physicians and 567 nurses. We found various differences with regard to the four topics. In most of the COPSOQ and the HSPSC-scales, physicians rated psychosocial working conditions and patient safety climate more positively than nurses. With regard to occupational safety, nurses
indicated higher occupational risks than physicians.
Conclusions:
The WorkSafeMed study combined the assessment of the four topics psychosocial working conditions, leadership, patient safety climate, and occupational safety climate in hospitals. Looking at the four topics provides an overview of where improvements in hospitals may be needed for nurses and physicians. Based on these results,
improvements in working conditions, patient safety climate, and occupational safety climate are required for health care professionals in German university hospitals – especially for nurses.
Objective
We aimed to investigate the proportion of young patients not returning to work (NRTW) at 1 year after ischemic stroke (IS) and during follow-up, and clinical factors associated with NRTW.
Methods
Patients from the Helsinki Young Stroke Registry with an IS occurring in the years 1994–2007, who were at paid employment within 1 year before IS, and with NIH Stroke Scale score ≤15 points at hospital discharge, were included. Data on periods of payment came from the Finnish Centre for Pensions, and death data from Statistics Finland. Multivariate logistic regression analyses assessed factors associated with NRTW 1 year after IS, and lasagna plots visualized the proportion of patients returning to work over time.
Results
We included a total of 769 patients, of whom 289 (37.6%) were not working at 1 year, 323 (42.0%) at 2 years, and 361 (46.9%) at 5 years from IS. When adjusted for age, sex, socioeconomic status, and NIH Stroke Scale score at admission, factors associated with NRTW at 1 year after IS were large anterior strokes, strokes caused by large artery atherosclerosis, high-risk sources of cardioembolism, and rare causes other than dissection compared with undetermined cause, moderate to severe aphasia vs no aphasia, mild and moderate to severe limb paresis vs no paresis, and moderate to severe visual field deficit vs no deficit.
Conclusions
NRTW is a frequent adverse outcome after IS in young adults with mild to moderate IS. Clinical variables available during acute hospitalization may allow prediction of NRTW.
Correction to: https://doi.org/10.1186/s12913-018-3862-7
In the original publication of this article, the authors missed that reverse coding was necessary for the item “Do you work separate from your colleagues?” before calculating the scale ‘social relations’. So they corrected the analysis accordingly. The results with the revised scale show that there are no longer any significant differences between nurses and physicians with regard to this scale.
Objective
To revise the German guidelines and recommendations for ensuring Good Epidemiological Practice (GEP) that were developed in 1999 by the German Society for Epidemiology (DGEpi), evaluated and revised in 2004, supplemented in 2008, and updated in 2014.
Methods
The executive board of the DGEpi tasked the third revision of the GEP. The revision was arrived as a result of a consensus-building process by a working group of the DGEpi in collaboration with other working groups of the DGEpi and with the German Association for Medical Informatics, Biometry and Epidemiology, the German Society of Social Medicine and Prevention (DGSMP), the German Region of the International Biometric Society (IBS-DR), the German Technology, Methods and Infrastructure for Networked Medical Research (TMF), and the German Network for Health Services Research (DNVF). The GEP also refers to related German Good Practice documents (e.g. Health Reporting, Cartographical Practice in the Healthcare System, Secondary Data Analysis).
Results
The working group modified the 11 guidelines (after revision: 1 ethics, 2 research question, 3 study protocol and manual of operations, 4 data protection, 5 sample banks, 6 quality assurance, 7 data storage and documentation, 8 analysis of epidemiological data, 9 contractual framework, 10 interpretation and scientific publication, 11 communication and public health) and modified and supplemented the related recommendations. All participating scientific professional associations adopted the revised GEP.
Conclusions
The revised GEP are addressed to everyone involved in the planning, preparation, execution, analysis, and evaluation of epidemiological research, as well as research institutes and funding bodies.
Objectives: Injury to major white matter pathways during language-area associated glioma surgery often leads to permanent loss of neurological function. The aim was to establish standardized tractography of language pathways as a predictor of language outcome in clinical neurosurgery.
Methods: We prospectively analyzed 50 surgical cases of patients with left perisylvian, diffuse gliomas. Standardized preoperative Diffusion-Tensor-Imaging (DTI)-based tractography of the 5 main language tracts (Arcuate Fasciculus [AF], Frontal Aslant Tract [FAT], Inferior Fronto-Occipital Fasciculus [IFOF], Inferior Longitudinal Fasciculus [ILF], Uncinate Fasciculus [UF]) and spatial analysis of tumor and tracts was performed. Postoperative imaging and the resulting resection map were analyzed for potential surgical injury of tracts. The language status was assessed preoperatively, postoperatively and after 3 months using the Aachen Aphasia Test and Berlin Aphasia Score. Correlation analyses, two-step cluster analysis and binary logistic regression were used to analyze associations of tractography results with language outcome after surgery.
Results: In 14 out of 50 patients (28%), new aphasic symptoms were detected 3 months after surgery. The preoperative infiltration of the AF was associated with functional worsening (cc = 0.314; p = 0.019). Cluster analysis of tract injury profiles revealed two areas particularly related to aphasia: the temporo-parieto-occipital junction (TPO; temporo-parietal AF, middle IFOF, middle ILF) and the temporal stem/peri-insular white matter (middle IFOF, anterior ILF, temporal UF, temporal AF). Injury to these areas (TPO: OR: 23.04; CI: 4.11 – 129.06; temporal stem: OR: 21.96; CI: 2.93 – 164.41) was associated with a higher-risk of persisting aphasia.
Conclusions: Tractography of language pathways can help to determine the individual aphasia risk profile presurgically. The TPO and temporal stem/peri-insular white matter were confirmed as functional nodes particularly sensitive to surgical injuries.
Aim:
The most suitable method for assessment of response to peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET) is still under debate. In this study we aimed to compare size (RECIST 1.1), density (Choi), Standardized Uptake Value (SUV) and a newly defined ZP combined parameter derived from Somatostatin Receptor (SSR) PET/CT for prediction of both response to PRRT and overall survival (OS).
Material and Methods:
Thirty-four NET patients with progressive disease (F:M 23:11; mean age 61.2 y; SD ± 12) treated with PRRT using either Lu-177 DOTATOC or Lu-177 DOTATATE and imaged with Ga-68 SSR PET/CT approximately 10–12 weeks prior to and after each treatment cycle were retrospectively analyzed. Median duration of follow-up after the first cycle was 63.9 months (range 6.2–86.2). A total of 77 lesions (2–8 per patient) were analyzed. Response assessment was performed according to RECIST 1.1, Choi and modified EORTC (MORE) criteria. In addition, a new parameter named ZP, the product of Hounsfield unit (HU) and SUVmean (Standard Uptake Value) of a tumor lesion, was tested. Further, SUV values (max and mean) of the tumor were normalized to SUV of normal liver parenchyma. Tumor response was defined as CR, PR, or SD. Gold standard for comparison of baseline parameters for prediction of response of individual target lesions to PRRT was change in size of lesions according to RECIST 1.1. For prediction of overall survival, the response after the first and second PRRT were tested.
Results:
Based on RECIST 1.1, Choi, MORE, and ZP, 85.3%, 64.7%, 61.8%, and 70.6% achieved a response whereas 14.7%, 35.3%, 38.2%, and 29.4% demonstrated PD (progressive disease), respectively. Baseline ZP and ZPnormalized were found to be the only parameters predictive of lesion progression after three PRRT cycles (AUC ZP 0.753; 95% CI 0.6–0.9, p 0.037; AUC ZPnormalized 0.766; 95% CI 0.6–0.9; p 0.029). Based on a cut-off-value of 1201, ZP achieved a sensitivity of 86% and a specificity of 67%, while ZPnormalized reached a sensitivity of 86% and a specificity of 76% at a cut-off-value of 198. Median OS in the total cohort was not reached. In univariate analysis amongst all parameters, only patients having progressive disease according to MORE after the second cycle of PRRT were found to have significantly shorter overall survival (median OS in objective responders not reached, in PD 29.2 months; p 0.015). Patients progressive after two cycles of PRRT according to ZP had shorter OS compared to those responding (median OS for responders not reached, for PD 47.2 months, p 0.066).
Conclusions:
In this explorative study, we showed that Choi, RECIST 1.1, and SUVmax-based response evaluation varied significantly from each other. Only patients showing progressive disease after two PRRT cycles according to MORE criteria had a worse prognosis while baseline ZP and
ZPnormalized performed best in predicting lesion progression after three cycles of PRRT.
Objective
Cyberknife robotic radiosurgery (RRS) provides single-session high-dose radiotherapy of brain tumors with a steep dose gradient and precise real-time image-guided motion correction. Although RRS appears to cause more radiation necrosis (RN), the radiometabolic changes after RRS have not been fully clarified. 18F-FET-PET/CT is used to differentiate recurrent tumor (RT) from RN after radiosurgery when MRI findings are indecisive. We explored the usefulness of dynamic parameters derived from 18F-FET PET in differentiating RT from RN after Cyberknife treatment in a single-center study population.
Methods
We retrospectively identified brain tumor patients with static and dynamic 18F-FET-PET/CT for suspected RN after Cyberknife. Static (tumor-to-background ratio) and dynamic PET parameters (time-activity curve, time-to-peak) were quantified. Analyses were performed for all lesions taken together (TOTAL) and for brain metastases only (METS). Diagnostic accuracy of PET parameters (using mean tumor-to-background ratio >1.95 and time-to-peak of 20 min for RT as cut-offs) and their respective improvement of diagnostic probability were analyzed.
Results
Fourteen patients with 28 brain tumors were included in quantitative analysis. Time-activity curves alone provided the highest sensitivities (TOTAL: 95%, METS: 100%) at the cost of specificity (TOTAL: 50%, METS: 57%). Combined mean tumor-to-background ratio and time-activity curve had the highest specificities (TOTAL: 63%, METS: 71%) and led to the highest increase in diagnosis probability of up to 16% p. – versus 5% p. when only static parameters were used.
Conclusions
This preliminary study shows that combined dynamic and static 18F-FET PET/CT parameters can be used in differentiating RT from RN after RRS.