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Human hearing loss is often accompanied by comorbidities like tinnitus. This perception of phantom sounds without external stimulation is affecting up to 15% of the adult population and can lead to psychological disorders like depression. Animal studies in rodents could show that tinnitus may not only be a result of hearing loss due to cochlear hair cell damage but can also be a consequence of synaptopathy at the inner hair cells already induced by moderate sound traumata (hidden hearing loss). In this study we investigate the synaptopathy previously shown in mice in our animal model, the Mongolian gerbil, and relate it to behavioral signs of tinnitus in this species. Tinnitus was induced by a mild monaural acoustic trauma leading to a monaural noise induced hearing loss in the animals quantified by auditory brainstem response audiometry. Behavioral signs of tinnitus percepts were detected by measurement of pre-pulse inhibition of the acoustic startle response in a gap-noise paradigm in about two-thirds of the animals. 14 days after trauma the cochleae of traumatized and non-traumatized ears were isolated and inner hair cell synapses were counted within several spectral regions of the cochlea. In the here presented preliminary data inner hair cell synaptopathy was only found in animals with behavioral signs of tinnitus, independent of type of hearing loss. On the other hand, animals with apparent hearing loss but without behavioral signs of tinnitus showed a reduction in amplitudes of auditory brainstem response waves I/II (cochlear nerve and dorsal cochlear nucleus) but no significant changes in the number of synapses at the inner hair cells. We conclude – in line with the literature – that hearing loss is caused by damage to the inner and / or outer hair cells but that the development of tinnitus, at least in our animal model is closely linked to synaptopathy at the inner hair cells.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis. Drug resistance is the major cause for therapeutic failure in PDAC patients with progressive disease. The mechanisms underlying resistance formation are complex and remain poorly understood.To gain insights into molecular changes during the formation of resistance to oncogenic MAPK pathway inhibition we utilized short-term passaged primary tumor cells from ten PDACs of genetically engineered mice. We followed gain and loss of resistance upon MEKi exposure and withdrawal by longitudinal integrative analysis of whole genome sequencing, whole genome bisulfite sequencing, RNA-sequencing and mass spectrometry data.We found that resistant cell populations under increasing MEKi treatment evolved by the expansion of a single clone but were not a direct consequence of known resistance-conferring mutations. Rather, resistant cells showed adaptive DNA hypermethylation of 209 and hypomethylation of 8 genomic sites, most of which overlap with regulatory elements known to be active in murine PDAC cells. Both DNA methylation changes and MEKi resistance were transient and reversible upon drug withdrawal. The effector caspase CASP3 is one of the 114 genes for which transcriptional downregulation inversely correlated with the methylation status of the associated DNA region. CASP3 inactivation in resistant cells led to attenuation of drug-induced apoptosis which could be reversed by DNA methyltransferase inhibition with remarkable sensitivity exclusively in the resistant cells.Overall, our data provide a context for characterization and targeting of epigenetically mediated resistance mechanisms in PDAC.

This narrative clinical review summarises the key evidence in support for the use of a hydro-responsive wound dressing, HydroTac (HRWD-2, PAUL HARTMANN AG, Germany) to address key aspects associated with the treatment of both acute and hard-to-heal wounds. This review demonstrates how HRWD-2 can be used in general to address the challenges presented by a wide range of wound types and skin injuries. It highlights the ability of HRWD-2 to regulate an optimal moist wound environment that promotes wound progression and healing. Key aspects covered in this review include the dressing's ability to: promote certain phases of the wound healing response (for example, re-epithelialisation) address the concepts and needs for wound progression as set out in the TIME wound management framework provide an optimal hydration level reduce tissue trauma and pain at dressing change.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial–mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.

MotivationHaplotype phasing approaches have been shown to improve accuracy of the search space of neoantigen prediction by determining if adjacent variants are located on the same chromosomal copy. However, the aneuploid nature of cancer cells as well as the admixture of different clones in tumor bulk sequencing data are challenging the current diploid based phasing algorithms. We present microphaser, a small-scale phasing approach to improve haplotyping variants in cancer samples. Microphaser aims to create a more accurate neopeptidome for downstream neoantigen prediction.ResultsMicrophaser achieves large concordance with state-of-the-art phasing-aware neoantigen prediction pipeline neoepiscope, with differences in edge cases and an improved filtering step.AvailabilityMicrophaser is written in the Rust programming language. It is made available via Github (https://github.com/koesterlab/microphaser)and Bioconda. The corresponding prediction pipeline (https://github.com/snakemake-workflows/dna-seq-neoantigen-prediction) has been written within the Snakemake workflow management system and can be deployed as part of the snakemake-workflows project.

Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. For example, melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a new dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor growth and plasticity and primes melanoma cells towards lineage-specific elimination.

Background Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. Methods We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6–40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. Findings Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12–28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of −0·22 mm per year (−0·41 to −0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means −0·10 per year, 95% CI −0·19 to −0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. Interpretation Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. Funding British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

Data analysis often entails a multitude of heterogeneous steps, from the application of various command line tools to the usage of scripting languages like R or Python for the generation of plots and tables. It is widely recognized that data analyses should ideally be conducted in a reproducible way. Reproducibility enables technical validation and regeneration of results on the original or even new data. However, reproducibility alone is by no means sufficient to deliver an analysis that is of lasting impact (i.e. sustainable) for the field, or even just one research group. We postulate that it is equally important to ensure adaptability and transparency. The former describes the ability to modify the analysis to answer extended or slightly different research questions. The latter describes the ability to understand the analysis in order to judge whether it is not only technically, but methodologically valid. Here, we analyze the properties needed for a data analysis to become reproducible, adaptable, and transparent, and show how the popular workflow management system Snakemake can be used to fulfill all these needs., This work was supported by the Netherlands Organisation for Scientific Research (NWO) (VENI grant 016.Veni.173.076, Johannes Köster), the German Research Foundation (SFB 876, Johannes Köster), and Google LLC (Vanessa Sochat and Johannes Köster).

AIMS: Right ventricular (RV) adaptation is a common finding in the athlete's heart. The aim of this study was to establish the extent of RV structural and functional adaptation in elite and academy professional footballers compared to age-matched controls.METHODS AND RESULTS: A total of 100 senior and 100 academy elite footballers and 20 senior and 19 academy age-matched controls were recruited. All participants underwent 2D, Doppler, tissue Doppler, and strain (ε) echocardiography of the right heart. Structural indices were derived and indexed allometrically for individual differences in body surface area. Standard RV function was assessed alongside peak RV ε and strain rate (SR). Senior football players had larger scaled RV structural parameters than academy players for the RV outflow (RVOTplax ) (32.7 ± 4.2 and 29.5 ± 4.0 mm(m2 )0.326 , P < 0.001), the proximal RV outflow (RVOT1 ) (26.6 ± 3.5 and 24.7 ± 3.9 mm(m2 )0.335 , P < 0.001), the basal RV inflow (RVD1 ) (33.1 ± 4.1 and 30.7 ± 3.2 mm(m2 )0.404 , P = 0.020), RV length (RVD3 ) (66.5 ± 6.1 and 62.9 ± 5.1 mm(m2 )0.431 , P < 0.001), and RV diastolic area (RVDarea ) (16.9 ± 2.6 and 15.7 ± 2.6 mm(m2 )0.735 , P < 0.001). Both academy and senior football players demonstrated larger scaled structural RV parameters in comparison with age-matched controls. Systolic SR (SRS) was lower in the senior players compared to academy players in the mid (-1.52 ± 0.49 and -1.41 ± 0.34 L/s, P = 0.019) and apical (-1.97 ± 0.74 and -1.72 ± 0.42 L/s, P = 0.025) wall regions, respectively.CONCLUSION: Right ventricular structural adaptation occurs in both senior and academy football players with senior players having larger RV dimensions. Although senior players have slightly lower peak SRS than academy players, all global ε and SR are within normal ranges.

The impact of prolonged exercise upon right ventricular (RV) function is poorly understood and to date no studies have utilized tissue-Doppler imaging (TDI). Thirty-five marathon runners (age range 18-50 years) volunteered for the study. Two-dimensional, pulsed Doppler, and TDI studies were performed one day before and immediately following race completion. Right and left ventricular (LV) longitudinal TDI myocardial velocities were acquired from the tricuspid annulus and mitral annulus, providing velocity data during systole (S'), early diastole (E'), and late diastole (A'). Transtricuspid and transmitral, early diastolic (E), and late diastolic (A) velocities and ratios were assessed using conventional pulsed-wave Doppler. RV and LV fractional area changes (FAC) were calculated from RV and LV end-diastolic and end-systolic areas recorded from 2D scans in a subsample (n = 23). RV myocardial velocities were unchanged pre-post race in S' (21.1 +/- 2.7 to 21.7 +/- 4.5 cm s(-1), P0.05), reduced in E' (23.3 +/- 3.5 to 19.9 +/- 5.3 cm s(-1), P0.05), increased in A' (19.1 +/- 3.6 to 23.7 +/- 6.8 cm s(-1), P0.05) with a resultant decline in E'/A' (1.28 +/- 0.36 to 0.94 +/- 0.45, P0.05). This pattern of data was mirrored in the LV. Similarly both pulsed-Doppler tricuspid and mitral E/A ratios decreased from pre- to postrace (P0.05). FAC for the RV and LV were unaltered postrace (P0.05). The impact of differing age, finishing time (173-330 min), hemodynamic loading and heart rate upon RV and LV function pre- to postrace was negligible. In conclusion, TDI and 2D data, for both the RV and LV demonstrated little change in systolic function after a marathon race. Conversely, a reduction in diastolic function was observed in both ventricles for which a mechanism has yet to be deduced.

The present study employed novel echocardiographic tools and cardiac markers to obtain a greater understanding of the aetiology and time course of altered cardiac function and cardiac damage following prolonged exercise and, in particular, the possible role of transient ischaemia within these phenomena. Fourteen runners in the 2004 London Marathon were assessed pre-, immediately post-, 1 h post- and 24 h postcompletion of the race. Left ventricular function was examined echocardiographically using 2-D, M-mode, tissue Doppler imaging and flow propagation velocity (Vp). Venous blood samples were analysed for N-terminal pro-B-type natriuretic peptide (proBNP), cardiac troponin T (cTnT) and ischaemia-modified albumin (IMA). Left ventricular (LV) diastolic filling was altered on completion of the race, as indicated by significant decreases in mean early to late diastolic myocardial wave (E′:A′) ratio and Vp (from 1.82 ± 0.9 to 1.32 ± 0.32, and from 67.5 ± 9.3 to 60.2 ± 8.2 cm s−1, respectively, P < 0.05), accompanied by an increase in proBNP (from 21.6 ± 11 to 47.08 ± 19.5 pg l−1, P < 0.05). The observed reduction in LV diastolic filling following completion of a marathon, unrelated to changes in heart rate or loading parameters, indicates an intrinsically mediated change in diastolic filling. Exercise-induced elevations in cTnT in nine individuals (range, 0.023–0.37 μg l−1) were indicative of minor cardiac damage. A significant reduction in IMA was observed after the marathon (from 63.68 ± 9.83 to 44.94 ± 16.13 Um l−1, P < 0.05), unrelated to the alterations in cardiac function, proBNP or cTnT. The absence of an elevation in IMA suggests that exercise-induced myocardial ischaemia did not occur and therefore could not explain the changes in cardiac function or biomarkers. Future studies in this area should investigate alternative diagnostic tools for the detection of transient ischaemia, and other potential mechanisms, in order to extend the understanding of this phenomenon.

We assessed segmental and global left ventricular (LV) diastolic function via tissue-Doppler imaging (TDI) as well as Doppler flow variables before and after a marathon race to extend our knowledge of exercise-induced changes in cardiac function. Twenty-nine subjects (age 18–62 year) volunteered to participate and were assessed pre- and post-race. Measurements of longitudinal plane TDI myocardial diastolic velocities at five sites on the mitral annulus included peak early myocardial tissue velocity (E′), peak late (or atrial) myocardial tissue velocity (A′) and the ratio E′/A′. Standard pulsed-wave Doppler transmitral and pulmonary vein flow indices were also recorded along with measurements of body mass, heart rate, blood pressures and cardiac troponin T (cTnT), a biomarker of myocyte damage. Pre- to post-race changes in LV diastolic function were analysed by repeated measures ANOVA. Delta scores for LV diastolic function were correlated with each other and alterations in indices of LV loading. Diastolic longitudinal segmental and mean TDI data were altered post-race such that the mean E′/A′ ratio was significantly depressed (1.51 ± 0.34 to 1.16 ± 0.35, P < 0.05). Changes in segmental and global TDI data were not related to an elevated post-race HR, a decreased post-race pre-load or an elevated cTnT. The pulsed wave Doppler ratio of peak early transmitral flow velocity (E)/peak late (or atrial) flow velocity (A) was also significantly reduced post-race (1.75 ± 0.46 to 1.05 ± 0.30, P < 0.05); however, it was significantly correlated with post-race changes in heart rate. The lack of change in E/E′ from pre- to post-race (3.4 ± 0.8 and 3.3 ± 0.7, respectively) suggests that the depression in diastolic function is likely to be due to altered relaxation of the left ventricle; however, the exact aetiology of this change remains to be determined.

Prognosis of the remaining battery life is an important and practical research area of rechargeable battery and smart grid. It has promising application prospect in such area as grid energy storage systems, electrical vehicles etc. In this paper, by analysing the lithium-ion battery information, the most influencing factors of lifetime are collected. Based on this, a novel system is proposed to predict the battery capacity loss using a model based on multivariate adaptive regression splines (MARS) method by an iterative technique. Unlike static models the proposed system is designed to overcome the problem of data sparseness at the beginning in application. It implements a reliable forecast of the battery life by using newly gained data iteratively, which increases the prediction accuracy noticeably. Experiments prove that the solution can predict battery life with high precision, and the prediction results meet the accuracy and stability requirements of practical application.

Background Three dimensional echo is a relatively new technique which may offer a rapid alternative for the examination of the right heart. However its role in patients with non-standard ventricular size or anatomy is unclear. This study compared volumetric measurements of the right ventricle in 25 patients with adult congenital heart disease using both cardiovascular magnetic resonance (CMR) and three dimensional echocardiography. Methods Patients were grouped by diagnosis into those expected to have normal or near-normal RV size (patients with repaired coarctation of the aorta) and patients expected to have moderate or worse RV enlargement (patients with repaired tetralogy of Fallot or transposition of the great arteries). Right ventricular end diastolic volume, end systolic volume and ejection fraction were compared using both methods with CMR regarded as the reference standard Results Bland-Altman analysis of the 25 patients demonstrated that for both RV EDV and RV ESV, there was a significant and systematic under-estimation of volume by 3D echo compared to CMR. This bias led to a mean underestimation of RV EDV by -34% (95%CI: -91% to + 23%). The degree of underestimation was more marked for RV ESV with a bias of -42% (95%CI: -117% to + 32%). There was also a tendency to overestimate RV EF by 3D echo with a bias of approximately 13% (95% CI -52% to +27%). Conclusions Statistically significant and clinically meaningful differences in volumetric measurements were observed between the two techniques. Three dimensional echocardiography does not appear ready for routine clinical use in RV assessment in congenital heart disease patients with more than mild RV dilatation at the current time.

Measurements and Monte Carlo-Simulations with different filling materials were performed. The purpose of this work was to establish valid numerical data for the dimensioning of radiation-shielding structures for Linacs in medical use (Bremsstrahlung up to 50 MV). The data are prepared to become implemented into the German regulations DIN 6847-2. Herewith the new sandwich technology can be established as an improved method for radiation shielding.

The present study examined the reproducibility of alterations in left ventricular function and cardiac biomarkers in a cohort of athletes following two marathons, one year apart. Eight participants in the 2004 and 2005 London Marathons were tested pre- and post-race via echocardiography and humoral analysis. Reductions in diastolic filling, unrelated to loading or heart rate, following both marathons were reproducible within individuals, which may be a function of exercise duration. In contrast, exercise-induced cardiac troponin release was inconsistent.

The precision of injection moulded high-class plastics products is the crucial factor. Especially the injection moulding of thick-walled polymer optics requires sophisticated measuring techniques for the control of the quality achieved and the analysis of the replication process. In particular the measuring range and the accuracy of the measuring instruments in combination with the sometimes large deviations between polymer geometry and ideal contour must be taken into account. The future target is the production of highly accurate polymer optics with an excellent process control. The paper discusses the use of an optical contact-free measuring technique for the analysis of injection moulded optical lenses.

We assessed segmental and global left ventricular (LV) diastolic function via tissue-Doppler imaging (TDI) as well as Doppler flow variables before and after a marathon race to extend our knowledge of exercise-induced changes in cardiac function. Twenty-nine subjects (age 18-62 year) volunteered to participate and were assessed pre- and post-race. Measurements of longitudinal plane TDI myocardial diastolic velocities at five sites on the mitral annulus included peak early myocardial tissue velocity (E'), peak late (or atrial) myocardial tissue velocity (A') and the ratio E'/A'. Standard pulsed-wave Doppler transmitral and pulmonary vein flow indices were also recorded along with measurements of body mass, heart rate, blood pressures and cardiac troponin T (cTnT), a biomarker of myocyte damage. Pre- to post-race changes in LV diastolic function were analysed by repeated measures ANOVA. Delta scores for LV diastolic function were correlated with each other and alterations in indices of LV loading. Diastolic longitudinal segmental and mean TDI data were altered post-race such that the mean E'/A' ratio was significantly depressed (1.51 +/- 0.34 to 1.16 +/- 0.35, P0.05). Changes in segmental and global TDI data were not related to an elevated post-race HR, a decreased post-race pre-load or an elevated cTnT. The pulsed wave Doppler ratio of peak early transmitral flow velocity (E)/peak late (or atrial) flow velocity (A) was also significantly reduced post-race (1.75 +/- 0.46 to 1.05 +/- 0.30, P0.05); however, it was significantly correlated with post-race changes in heart rate. The lack of change in E/E' from pre- to post-race (3.4 +/- 0.8 and 3.3 +/- 0.7, respectively) suggests that the depression in diastolic function is likely to be due to altered relaxation of the left ventricle; however, the exact aetiology of this change remains to be determined.

The present study examined the relationship between LV (left ventricular) function, markers of cardiac-specific damage and markers of oxidative stress in recreational runners following a marathon. Runners (n=52; 43 male and nine female; age, 35±10 years; height, 1.74±0.08 m; body mass, 75.9±8.9 kg) were assessed pre- and immediately post-marathon. LV function was assessed using standard M-mode two-dimensional Doppler echocardiography and TDI (tissue-Doppler imaging) echocardiography. Serum was analysed for cTnT (cardiac troponin-T), TEAC (Trolox equivalent antioxidant capacity; a measure of total antioxidant capacity), MDA (malondealdehyde) and 4-HNE (4-hydroxynonenal). A strong relationship was observed between standard and TDI echocardiography for all functional measures. Diastolic function was altered post-marathon characterized by a reduction in E (peak early diastolic filling: 0.79±0.11 compared with 0.64±0.16 cm/s; P