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Kabuki syndrome is a Mendelian disorder of the epigenetic machinery characterized by typical dysmorphic features, intellectual disability, and postnatal growth deficiency. Pathogenic variants in the genes encoding the chromatin modifiers KMT2D and KDM6A are responsible for Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), respectively. In addition, 11 cases of KS1 caused by mosaic variants in KMT2D have been reported in the literature. Some of these individuals display milder craniofacial and growth phenotypes, and most do not have congenital heart defects. We report the case of an infant with severe hypoplastic left heart syndrome with mitral atresia and aortic atresia (HLHS MA-AA), pulmonary vein stenosis, and atypical facies with a somatic mosaic de novo nonsense variant in KMT2D (c.8200C>T, p.R2734*) identified on trio exome sequencing of peripheral blood and present in 11.2% of sequencing reads. KS was confirmed with EpiSign, a diagnostic genome-wide DNA methylation platform used to identify epigenetic signatures. This case suggests that use of this newly available clinical test can guide the interpretation of low-level mosaic variants identified through sequencing and suggests a new lower limit of mosaicism in whole blood required for a diagnosis of KS., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

The purification of extracellular vesicles (EVs) remains a major hurdle in the progression of fundamental research and the commercial application of EV-based products. In this study, we evaluated the potential of heparin affinity chromatography (HAC) to purify neural stem cell-derived EVs as part of a multistep process. Bind-elute chromatography, such as HAC, is an attractive method of purification because it is highly scalable, robust and can be automated. Our findings support an interaction between EVs and heparin. The recovery of EVs using HAC based on particle counts was a minimum of 68.7%. We found HAC could remove on average 98.8% and 99.0% of residual protein and DNA respectively. In addition to EV purification, HAC was used to separate EVs into three populations based on their affinity to the heparin column. Within these populations, we detected differences in the expression of the exosome-associated protein TSG101 and the tetraspanin immunophenotype. However, the significance of these observations is not clear. Overall HAC shows promise as a potential purification method to capture EVs and this study proposes a novel application of HAC for EV fractionation. Moving forward, a better understanding of the heparin-EV interaction would be required before HAC can be more widely adopted for these applications., Competing Interests: Declaration of competing interest Authors, Samantha Thomas and Paul Hole, are currently employees at ReNeuron who provided the EV TFF material for this study. ReNeuron also partially funded the work in this study., (Copyright © 2022. Published by Elsevier B.V.)

For thousands of years, carbon ink has been used as a black color pigment for writing and painting purposes. However, recent discoveries of nanocarbon materials, including fullerenes, carbon nanotubes, graphene, and their various derivative forms, together with the advances in large-scale synthesis, are enabling a whole new generation of carbon inks that can serve as an intrinsically programmable materials platform for developing advanced functionalities far beyond color. The marriage between these multifunctional nanocarbon inks with modern printing technologies is facilitating and even transforming many applications, including flexible electronics, wearable and implantable sensors, actuators, and autonomous robotics. This review examines recent progress in the reborn field of carbon inks, highlighting their programmability and multifunctionality for applications in flexible electronics and stimuli-responsive devices. Current challenges and opportunities will also be discussed from a materials science perspective towards the advancement of carbon ink for new applications beyond color., (© 2021 Wiley-VCH GmbH.)

Background: The aims of this study were to investigate the dynamic changes in the vena contracta (VC) and proximal isovelocity surface area (PISA) through systole in patients with hypoplastic left heart syndrome and tricuspid regurgitation and to identify the stage of systole (early, mid, or late) in which VC and PISA radius are optimal., Methods: Twenty-eight patients with hypoplastic left heart syndrome were prospectively studied using continuous two-dimensional (2D) and three-dimensional (3D) echocardiography. Two-dimensional VC width, 3D VC area, and PISA radii (2D and 3D) were measured frame by frame throughout systole. The maximal 2D VC width, 3D VC area, and PISA radii in the first, middle, and last thirds of systole were compared, and correlations were explored with 3D tricuspid annular areas, right atrial volumes, and right ventricular volumes., Results: In all, 35 data sets that met inclusion criteria were analyzed. On frame-by-frame analysis, maximal 2D VC width and 3D VC area were found in the first third of systole in 17% and 20% of studies, in the second third in 34% and 31%, and in the final third in 49% and 49%. Similarly, the maximal 2D and 3D PISA radii were found in the first third of systole in 26% and 17% of studies, in the second third in 28% and 34%, and in the final third in 46% and 49%., Conclusions: In hypoplastic left heart syndrome, detailed temporal analysis of tricuspid regurgitation-associated VC and PISA by 2D and 3D echocardiography reveals no reliable pattern predicting when in systole these parameters peak. Frame-by-frame measurement is necessary for identification of maximal VC and PISA radius on 2D and 3D color Doppler echocardiography because the severity of tricuspid regurgitation could be underestimated because of temporal variability in VC and PISA., (Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the rate of secondary malignancies in long-term survivors with ovarian cancer., Methods: Long-term survivors with ovarian cancer (survival ≥8 years after initial diagnosis) with multiple malignancies were identified within the Tumorbank Ovarian Cancer and our study 'Carolin meets HANNA - Holistic Analyses of Long-term Survivors with Ovarian Cancer'., Results: Of a total of 225 long-term survivors with ovarian cancer, 36 patients (16%) had at least one more cancer diagnosis before, concomitant with, or after, ovarian cancer. Median age was 52.5 years (range 37-79). A total of 60% were diagnosed with stage III/IV and most tumors were high-grade (88.6%), as well as of serous histology (63.9%). Median overall survival was 10 years (range 8-19). Secondary cancer after ovarian cancer was found in 17 long-term survivors (7.6%). Breast cancer was the most frequent secondary malignancy. Median duration between diagnosis of primary ovarian cancer and secondary cancer diagnosis was 78.5 months (range 12-220). BRCA was tested in 11 patients with seven patients being BRCA1 and one patient BRCA2 positive. Secondary cancers were detected by screening in 35.3% and self-detected in 29.4% of patients (breast self-examination)., Conclusion: A secondary malignancy was diagnosed in 7.6% of long-term survivors. Routine follow-up and cancer screening should be performed in long-term ovarian cancer survivors., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The COVID-19 pandemic is posing major challenges to the health care sector. This scoping review compiles evidence concerning changes to health care service availability and utilisation as well as possible impacts on health for selected groups of chronically ill people in Germany. The focus is on cancer, cardiovascular diseases, diabetes mellitus and mental disorders. Most empirical data available concerned inpatient care and showed a clear decline in the utilisation of inpatient treatments in March and April 2020 in the areas of oncology and cardiology as well as in mental health. For cardiovascular emergencies such as heart attack and stroke, a decline was observed especially regarding less serious cases. Although there were indications of treatment delays, there was no evidence thus far that emergency care had been generally compromised due to adjustments to inpatient care capacities. In the outpatient setting, extensive adjustments to health care services availability were observed for all disease groups considered. Overall, very limited empirical data were available. In particular, hardly any data were available on how changes in care impacted population health. There is an urgent need for continuous surveillance and evaluation based on health care and epidemiological data., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

Background: Vector flow mapping is an emerging echocardiographic method allowing for investigation of intracardiac blood flow mechanics, wall shear stress (WSS), and energy loss (EL). We hypothesized that alterations in EL and WSS will differ among subjects with hypertrophic (HCM), dilated (DCM) cardiomyopathy, and normal controls., Methods: Echocardiograms were prospectively performed with the ProSound F75CV (Hitachi HealthCare., Tokyo, Japan) on all subjects. 2D color Doppler cine loop images were obtained from apical 5 and the apical long axis views and stored digitally. Measurements were averaged over three cardiac cycles using VFM software to derive flow patterns, WSS, and EL. Standard left ventricular (LV) systolic and diastolic functional parameters were also obtained., Results: A total of 85 subjects, 22 with HCM (age 18 ± 9 yrs.), 18 DCM (age 18 ± 9 yrs.), and 45 age and gender matched controls were included in the study. Diastolic wall shear stress was found significantly different in HCM (0.004 ± 0.185 N/m 2 ) compared with DCM (0.397 ± 0.301 N/m 2 , P < 0.001), and controls (0.175 ± 0.255 N/m 2 , P = 0.027). Furthermore, indexed systolic EL was found to be significantly elevated in HCM (13.91 ± 13.17 mW/m 2 /m 3 ) compared with DCM (8.17 ± 9.77 mW/m 2 /m 3 , P < 0.001), but not controls (6.45 ± 7.47 mW/m 2 /m 3 )., Conclusion: Differences in abnormal ventricular mechanics observed in HCM and DCM are reflected in both EL and WSS, and are suggestive that changes in energetic parameters may represent novel indices of ventricular dysfunction., (© 2020 The Authors.)

Like molecules of DNA, carbon nanotubes (CNTs) can display a variety of structures, but all conduct electrons and feature unique optical properties. In this perspective article, we highlight several recent works that bridge these two seemingly distant worlds. We illustrate the largely untapped potential of CNTs for biological research by exploring several developing biomedical applications utilizing nanotube semiconductors, including field effect transistor biosensors that couple high sensitivity with selectivity, and fluorophores for deep-tissue imaging whose excitation and emission wavelengths can be tuned throughout the near-IR II window simply by using defect chemistry.

In Germany, approximately 227,000 women and 249,000 men developed cancer in 2014, and nearly 223,000 patients died from the disease that year. Many cancers are curable or have a very good prognosis when they are diagnosed at an early stage. This is where the concept of early detection examinations comes into play.This article describes the current conditions of and participation in examinations for the early detection of cervical, breast, skin, prostate, and colon cancer as provided by Germany's statutory health services. Participation was derived from claims data from the statutory health insurance system as well as from Germany's mammography screening program (MSP). The survey "German Health Update" (GEDA 2014/2015-EHIS) served as an additional data source. According to the claims data and considering the intended intervals, participation quotas among insured persons who are entitled to participate lie between 16% (colonoscopy) and 48% (Pap test). In 2015, 51.5% of invited women participated in the MSP. The results according to self-reports of the GEDA survey lie in part substantially higher. The results according to the claims data, the MSP, as well as the self-reports suggest that a large part of the population utilizes the examinations. Colon and cervical cancer examinations will be expanded as organized and quality-assured early detection programs with regular invitations and information on benefits and risks. These efforts should contribute to reaching eligible people who have thus far not participated.

The nature of copper phosphate minerals in drinking water distribution systems has remained largely unsolved despite being an important link to reducing cuprosolvency. Chemical equilibrium modeling has also largely failed to accurately predict soluble copper in the presence of orthophosphate. The objective of this work was to develop and validate an empirical copper solubility model that considered pH, dissolved inorganic carbon (DIC), and orthophosphate from a series of bench-scale copper precipitation experiments. An empirical model was constructed that allows for the determination of copper levels in a system given pH, DIC, and orthophosphate data. The predictive reliability of this model was assessed by evaluating a collection of cuprosolvency data from two decades of research and field observations and water treatment reports. The tests yielded a firm correlation between predicted and observed copper levels attested by a regression coefficient of 0.86 for a total of 851 observations.

Objectives: Large temporal and geographical variation in survival rates estimated from epidemiological cancer registries coupled with heterogeneity in death certificate only (DCO) notifications makes it difficult to interpret trends in survival. The aim of our study is to introduce a method for estimating such trends while accounting for heterogeneity in DCO notifications in a cancer site-specific manner., Study Design and Setting: We used the data of 4.0 million cancer cases notified in 14 German epidemiological cancer registries. Annual 5-year relative survival rates from 2002 through 2013 were estimated, and proportions of DCO notifications were recorded. "DCO-excluded" survival rates were regressed on DCO proportions and calendar years using a mixed linear model with cancer registry as a random effect. Based on this model, trends in survival rates were estimated for Germany at 0% DCO., Results: For most cancer sites and age groups, we estimated significant positive trends in survival. Age-standardized survival for all cancers combined increased by 7.1% units for women and 10.8% units for men., Conclusion: The described method could be used to estimate trends in cancer survival based on the data from epidemiological cancer registries with differing DCO proportions and with changing DCO proportions over time., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Previous epidemiologic studies on AML have been limited by the rarity of the disease. Here, we present population level data on survival of patients with AML in Germany and the United States (US). Data were extracted from 11 population-based cancer registries in Germany and the Surveillance, Epidemiology, and End Results (SEER13) database in the US. Patients diagnosed with AML in 1997-2011 were included. Period analysis was used to estimate 5-year relative survival (RS) and trends in survival in the early 21st century. Overall 5-year age-adjusted RS for patients with AML in 2007-2011 was greater in Germany than in the US at 22.8% and 18.8%, respectively. Five-year RS was higher in Germany than in the US at all ages, with particularly large differences at ages 15-24 for whom 5-year RS was 64.3% in Germany and 55.0% in the US and 35-44, with 5-year RS estimates of 61.8% in Germany and 46.6% in the US. Most of the difference in 5-year RS was due to higher 1-year RS, with overall 1-year RS estimates of 47.0% in Germany and 38.5% in the US. A small increase in RS was observed between 2003-2005 and 2009-2011 in both countries, but no increase in survival was observed in either country for ages 75+. To our knowledge, this is the first detailed description of AML survival in Germany. Comparison to the US suggests that further analysis into risk factors for poor outcomes in AML in the US may be useful in improving survival., (© 2016 UICC.)

Critical illness myopathy (CIM) is associated with severe muscle atrophy and fatigue in affected patients. Apoptotic signaling is involved in atrophy and is elevated in muscles from patients with CIM. In this study we investigated underlying mechanisms of apoptosis-related pathways in muscles with different fiber type composition in a rat model of CIM using denervation and glucocorticoid administration (denervation and steroid-induced myopathy, DSIM). Soleus and tibialis anterior (TA) muscles showed severe muscle atrophy (40-60% of control muscle weight) and significant apoptosis in interstitial as well as myofiber nuclei that was similar between the two muscles with DSIM. Caspase-3 and -8 activities, but not caspase-9 and -12, were elevated in TA and not in soleus muscle, while the caspase-independent proteins endonuclease G (EndoG) and apoptosis inducing factor (AIF) were not changed in abundance nor differentially localized in either muscle. Anti-apoptotic proteins HSP70, -27, and apoptosis repressor with a caspase recruitment domain (ARC) were elevated in soleus compared to TA muscle and ARC was significantly decreased with induction of DSIM in soleus. Results indicate that apoptosis is a significant process associated with DSIM in both soleus and TA muscles, and that apoptosis-associated processes are differentially regulated in muscles of different function and fiber type undergoing atrophy due to DSIM. We conclude that interventions combating apoptosis with CIM may need to be directed towards inhibiting caspase-dependent as well as -independent mechanisms to be able to affect muscles of all fiber types.

Purpose: Germany lacks an up-to-date assessment of the cancer burden attributable to alcohol. Therefore, cancer incidence attributable to this exposure was estimated for colorectal, liver, breast, and upper aerodigestive tract (UADT) cancer. Additionally, the impact of alcohol on UADT cancer was analyzed by smoking status, to account for synergistic interactions between these two risk factors., Methods: Alcohol consumption and smoking prevalence from a nationwide survey in Germany 2008-2011 were combined with relative risks of incident cancer from meta-analyses to obtain population attributable risks (PARs), indicating the proportion of cancers that could be avoided by eliminating a risk factor. Each PAR was multiplied with the respective cancer incidence for 2010 to calculate the absolute number of attributable cases., Results: In Germany, for the year 2010, approximately 13,000 incident cancer cases could be attributed to alcohol consumption (3% of total cases). PAR was highest for esophageal cancer (men: 47.6% and women: 35.8%) and lowest for colorectal cancer in men (9.7%) and breast cancer in women (6.6%). Among women, moderate consumption levels account for the greatest PAR overall, whereas heavy drinking contributes considerably to overall PAR among men. Additionally, moderate-to-heavy drinking among smokers substantially contributes to the overall PAR of UADT cancers compared to drinking among non-smokers., Conclusion: In Germany, a substantial proportion of cases of common cancers can be attributed to alcohol consumption, even when consumed at moderate levels. Alcohol consumption with concurrent tobacco smoking is especially important for cancers of the UADT. These findings strengthen the rationale for prevention measures that address exposure at all levels.

The monitoring of cancer survival by population-based cancer registries is a prerequisite to evaluate the current quality of cancer care. Our study provides 1-, 5- and 10-year relative survival as well as 5-year relative survival conditional on 1-year survival estimates and recent survival trends for Germany using data from 11 population-based cancer registries, covering around one-third of the German population. Period analysis was used to estimate relative survival for 24 common and 11 less common cancer sites for the period 2007-2010. The German and the United States survival estimates were compared using the Surveillance, Epidemiology and End Results 13 database. Trends in cancer survival in Germany between 2002-2004 and 2008-2010 were described. Five-year relative survival increased in Germany from 2002-2004 to 2008-2010 for most cancer sites. Among the 24 most common cancers, largest improvements were seen for multiple myeloma (8.0% units), non-Hodgkin lymphoma (6.2% units), prostate cancer (5.2% units) and colorectal cancer (4.6% units). In 2007-2010, the survival disadvantage in Germany compared to the United States was largest for cancers of the mouth/pharynx (-11.0% units), thyroid (-6.8% units) and prostate (-7.5% units). Although survival estimates were much lower for elderly patients in both countries, differences in age patterns were observed for some cancer sites. The reported improvements in cancer survival might reflect advances in the quality of cancer care on the population level as well as increased use of screening in Germany. The survival differences across countries and the survival disadvantage in the elderly require further investigation., (© 2014 UICC.)

Background: The population-level impact of modifiable postmenopausal breast cancer risk factors is incompletely understood, especially regarding potential heterogeneity by estrogen receptor (ER) and progesterone receptor (PR) status., Methods: Using data on 3074 cases and 6386 controls from a population-based case-control study of postmenopausal breast cancer conducted in Germany between 2002 and 2005, we calculated multivariable-adjusted odds ratios and population attributable risks (PARs) for modifiable and non-modifiable risk factors. We examined overall postmenopausal invasive breast cancer as well as tumor ER/PR subtypes. A bootstrap method provided estimates of 95% confidence intervals (95%CIs)., Results: The summary PARs (95%CIs) for non-modifiable risk factors (age at menarche, age at menopause, parity, benign breast disease, and family history of breast cancer) were 37.2% (27.1-47.2%) regarding overall invasive tumors, 36.5% (23.3-47.6%) regarding ER+/PR+ tumors, 47.9% (26.4-64.4%) regarding ER+/PR- tumors, and 31.1% (4.0-51.9%) regarding ER-/PR- tumors. Of the modifiable risk factors (hormone therapy (HT) use, physical inactivity, BMI, alcohol consumption), HT use and physical inactivity had the highest impact with PARs of 19.4% (15.9-23.2%) and 12.8% (5.5-20.8%), respectively, regarding overall invasive tumors. For ER+/PR+ tumors, the corresponding PARs were 25.3% (20.9-29.7%) and 16.6% (7.0-26.0%). The summary PARs (95%CIs) for HT use and physical inactivity together were 29.8% (21.8-36.9%) and 37.9% (30.6-46.2%) regarding overall invasive and ER+/PR+ tumors, respectively., Conclusions: The population-level impact of modifiable risk factors appears to be comparable to that of non-modifiable risk factors. Alterations in HT use and physical inactivity could potentially reduce postmenopausal invasive breast cancer incidence in Germany by nearly 30%, with the largest potential for reduction among ER+/PR+ tumors, the most frequently diagnosed subtype., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) appear to influence breast cancer risk and are hypothesized to mediate the effects of several cancer risk factors that depend on menopausal status. We investigated associations among cancer risk factors and plasma IGF-I and IGFBP-3 in 882 healthy control women (426 premenopausal, 456 postmenopausal) from two population-based breast cancer case–control studies. Interactions with menopausal status were statistically tested. We observed associations with non-modifiable (age, benign breast disease) and modifiable factors [body mass index (BMI), physical activity, smoking habits, alcohol consumption]. Furthermore, we demonstrated statistical interactions with menopausal status. Premenopausal IGFBP-3 levels increased and postmenopausal levels decreased with age (p-interaction = 0.001). Overweight postmenopausal women had higher IGF-I (p = 0.049) and IGFBP-3 (p = 0.005) levels than women with lower BMI. Postmenopausal IGF-I levels were positively associated with physical activity (p-trend = 0.012, p-interaction = 0.050). Postmenopausal current smokers had lower IGF-I (p = 0.014) and IGFBP-3 levels (p = 0.011). Increasing alcohol consumption was associated with lower premenopausal IGF-I (p-trend = 0.002, p-interaction = 0.004) and higher postmenopausal IGFBP-3 levels (p = 0.019). Benign breast disease was associated with higher premenopausal (p = 0.044) and postmenopausal (p = 0.002) IGF-I levels. IGF-I and/or IGFBP-3 potentially mediate changes in breast cancer risk associated with BMI, benign breast disease, and perhaps alcohol consumption. Other observed associations suggest that neither IGF-I nor IGFBP-3 alone acts as mediator. Consideration of menopausal status may help disentangle carcinogenic pathways involving IGF proteins.

The availability of multiple teleost (bony fish) genomes is providing unprecedented opportunities to understand the diversity and function of gene duplication events using comparative genomics. Here we describe the cloning and functional characterization of two novel vitamin D receptor (VDR) paralogs from the freshwater teleost medaka (Oryzias latipes). VDR sequences were identified through mining of the medaka genome database in which gene organization and structure was determined. Two distinct VDR genes were identified in the medaka genome and mapped to defined loci. Each VDR sequence exhibits unique intronic organization and dissimilar 5' untranslated regions, suggesting they are not isoforms of the same gene locus. Phylogenetic comparison with additional teleosts and mammalian VDR sequences illustrate that two distinct clusters are formed separating aquatic and terrestrial species. Nested within the teleost cluster are two separate clades for VDRalpha and VDRbeta. The topology of teleost VDR sequences is consistent with the notion of paralogous genes arising from a whole genome duplication event prior to teleost radiation. Functional characterization was conducted through the development of VDR expression vectors including Gal4 chimeras containing the yeast Gal4 DNA binding domain fused to the medaka VDR ligand binding domain and full-length protein. The common VDR ligand 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)(2)D(3)] resulted in significant transactivation activity with both the Gal4 and full-length constructs of medaka (m) VDRbeta. Comparatively, transactivation of mVDRalpha with 1alpha,25(OH)(2)D(3) was highly attenuated, suggesting a functional divergence between these two nuclear receptor paralogs. We additionally demonstrate through coactivator studies that mVDRalpha is still functional; however, it exhibits a different sensitivity to 1alpha,25(OH)(2)D(3), compared with VDRbeta. These results suggest that in mVDRalpha and VDRbeta have undergone a functional divergence through a process of sub- and/or neofunctionalization of VDR nuclear receptor gene pairs.