Resonant generation of propagating second-harmonic spin waves in nano-waveguides.

Generation of second-harmonic waves is one of the universal nonlinear phenomena that have found numerous technical applications in many modern technologies, in particular, in photonics. This phenomenon also has great potential in the field of magnonics, which considers the use of spin waves in magnetic nanostructures to implement wave-based signal processing and computing. However, due to the strong frequency dependence of the phase velocity of spin waves, resonant phase-matched generation of second-harmonic spin waves has not yet been achieved in practice. Here, we show experimentally that such a process can be realized using a combination of different modes of nano-sized spin-wave waveguides based on low-damping magnetic insulators. We demonstrate that our approach enables efficient spatially-extended energy transfer between interacting waves, which can be controlled by the intensity of the initial wave and the static magnetic field.

The first comprehensive population size estimations for the highly endangered largest diving beetle Dytiscus latissimus in Europe.

Dytiscus latissimus (Coleoptera Dytiscidae) is an endangered diving beetle throughout its range. It is one of the two species of Dytiscidae listed in Annex II of the Habitats Directive, IUCN red list and in many national level legislations and therefore strictly protected. The conservation of endangered species first of all requires an assessment of their population size. Until now, a method has not been developed for estimating the size of D. latissimus populations. The article summarizes the results of two studies carried out independently in Germany and Latvia. Both studies were carried out in one water body used recapture method but with a different spatial placement of traps, which, according to our data, is an important factor in population estimation. We evaluated Jolly-Seber and Schnabel approaches of estimating aquatic beetle's populations and found that confidence intervals obtained by different methods in our research do not differ significantly, but combination of both models provide the most accurate estimates of population dynamics. As part of the study, we concluded that the populations of Dytiscus latissimus are relatively closed, so we accept that the Schnabel estimate shows more accurate data. By fixing the places of capture of each individual, it was found that females live mainly locally, and males actively move within the water body. This aspect indicates the advantage of the spatial placement of traps compared to the use of transects. The results of our study show a significantly higher number of both captured and recaptured males Such a sex ratio may indicate both a greater activity of males and differences in the sex ratio in the population. The study confirmed that environmental changes, such as the water level in a water body, can also significantly affect the result of a population assessment. In the frame of D. latissimus monitoring, to obtain an objective estimation of the species population size we recommend using four traps for each 100 m of water body shoreline with 4-8 censuses, dependently on the recapture rate.

Exchange biased delta-E effect enables the detection of low frequency pT magnetic fields with simultaneous localization.

Delta-E effect sensors are based on magnetoelectric resonators that detune in a magnetic field due to the delta-E effect of the magnetostrictive material. In recent years, such sensors have shown the potential to detect small amplitude and low-frequency magnetic fields. Yet, they all require external magnetic bias fields for optimal operation, which is highly detrimental to their application. Here, we solve this problem by combining the delta-E effect with exchange biased multilayers and operate the resonator in a low-loss torsion mode. It is comprehensively analyzed experimentally and theoretically using various kinds of models. Due to the exchange bias, no external magnetic bias fields are required, but still low detection limits down to [Formula: see text] at 25 Hz are achieved. The potential of this concept is demonstrated with a new operating scheme that permits simultaneous measurement and localization, which is especially desirable for typical biomedical inverse solution problems. The sensor is localized with a minimum spatial resolution of 1 cm while measuring a low-frequency magnetic test signal that can be well reconstructed. Overall, we demonstrate that this class of magnetic field sensors is a significant step towards first biomedical applications and compact large number sensor arrays.

Teaching breast ultrasound skills including core-needle biopsies on a phantom enhances undergraduate student's knowledge and learning satisfaction.

PURPOSE: To investigate whether a training program on breast ultrasound skills including core-needle biopsies to undergraduate students can improve medical knowledge and learning satisfaction. METHODS: Medical students attending mandatory classes at the Medical School of the University of Saarland received a supplemental theoretical and hands-on training program on ultrasound (US) breast screening and on US-guided core-needle biopsy using an agar-agar phantom. Experienced breast specialists and ultrasound examiners served as trainers applying Peyton's 4-step training approach. The students' theoretical knowledge and hands-on skills were tested before and after the training program, using a multiple-choice questionnaire (MCQ), the Objective Structured Clinical Examination (OSCE) and a student curriculum evaluation. RESULTS: The MCQ results showed a significant increase of the student's theoretical knowledge (50.2-75.2%, p < 0.001). After the course, the OSCE showed a mean total of 17.3/20 points (86.5%), confirming the practical implementation of the new skills. The student curriculum evaluation in general was very positive. A total of 16/20 questions were rated between 1.2 and 1.7 (very good) and 3 questions were rated as 2.1 (good). CONCLUSION: Undergraduate student's medical education can be enhanced by teaching breast US skills.

An Assessment of Earth's Climate Sensitivity Using Multiple Lines of Evidence.

We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO2, characterized by an effective sensitivity S. This evidence includes feedback process understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density function (PDF) for S given all the evidence, including tests of robustness to difficult-to-quantify uncertainties and different priors. The 66% range is 2.6-3.9 K for our Baseline calculation and remains within 2.3-4.5 K under the robustness tests; corresponding 5-95% ranges are 2.3-4.7 K, bounded by 2.0-5.7 K (although such high-confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S, in particular using comprehensive models and process understanding to address limitations in the traditional forcing-feedback paradigm for interpreting past changes.

Subtle ocular movements in a patient with brain death.

Introduction and Case Presentation: Brain death can be associated with limb movements that are attributed to spinal reflexes. Although head/face movements have been rarely reported, no case of overt eye movements in brain death has been documented. We report a case of a patient with subtle eye movements whose exam was otherwise consistent with brain death. The presence of eye movements delayed pronouncing the patient as brain dead and delayed organ donation. We agree with American Academy of Neurology Position statement from 2019 that brain death does not mean demise of every neuron. Discussion: This case raises important questions about the types of movements that should be "allowed" during the determination of brain death to avoid delays in diagnosis.

Laparoscopic Liver Resection: A South American Experience with 2887 Cases.

BACKGROUND: Laparoscopic liver resections (LLR) have been increasingly performed in recent years. Most of the available evidence, however, comes from specialized centers in Asia, Europe and USA. Data from South America are limited and based on single-center experiences. To date, no multicenter studies evaluated the results of LLR in South America. The aim of this study was to evaluate the experience and results with LLR in South American centers. METHODS: From February to November 2019, a survey about LLR was conducted in 61 hepatobiliary centers in South America, composed by 20 questions concerning demographic characteristics, surgical data, and perioperative results. RESULTS: Fifty-one (83.6%) centers from seven different countries answered the survey. A total of 2887 LLR were performed, as follows: Argentina (928), Brazil (1326), Chile (322), Colombia (210), Paraguay (9), Peru (75), and Uruguay (8). The first program began in 1997; however, the majority (60.7%) started after 2010. The percentage of LLR over open resections was 28.4% (4.4-84%). Of the total, 76.5% were minor hepatectomies and 23.5% major, including 266 right hepatectomies and 343 left hepatectomies. The conversion rate was 9.7%, overall morbidity 13%, and mortality 0.7%. CONCLUSIONS: This is the largest study assessing the dissemination and results of LLR in South America. It showed an increasing number of centers performing LLR with the promising perioperative results, aligned with other worldwide excellence centers.

Everolimus- vs. novolimus-eluting bioresorbable scaffolds in patients with acute coronary syndrome.

BACKGROUND: Limited data exist on bioresorbable scaffolds (BRS) in patients with acute coronary syndrome (ACS). The aim of the present study was to evaluate novolimus-eluting BRS (DESolve) as interventional treatment for patients with ACS, and to compare its 12-month outcomes with the everolimus-eluting bioresorbable scaffolds (Absorb). METHODS: In this retrospective study, patients with ACS (including unstable angina pectoris, ST-segment elevation myocardial infarction, or non-ST-segment elevation myocardial infarction) treated with either the Absorb or the DESolve BRS were evaluated in a 1:1 matched-pair analysis. Major adverse cardiac events (MACE), including death, myocardial infarction, and target lesion revascularization, were evaluated as a major endpoint. The occurrence of scaffold thrombosis was also assessed. RESULTS: A total of 102 patients were eligible for this analysis. The rate of MACE at 12 months was comparable between the Absorb and the DESolve group (8.3% vs. 6.8%, p = 0.738). The occurrence of target lesion revascularization (6.2% vs. 4.7%; p = 0.700) and scaffold thrombosis (4.1% vs. 2.1%; p = 0.580) was comparable as well. All instances of scaffold thrombosis occurred within 30 days of the index procedure. CONCLUSION: In this study, similar 12-month event rates were observed for both BRS types after implantation for the treatment of ACS.

Fetal heart rate variability responsiveness to maternal stress, non-invasively detected from maternal transabdominal ECG.

PURPOSE: Prenatal stress (PS) during pregnancy affects in utero- and postnatal child brain-development. Key systems affected are the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS). Maternal- and fetal ANS activity can be gauged non-invasively from transabdominal electrocardiogram (taECG). We propose a novel approach to assess couplings between maternal (mHR) and fetal heart rate (fHR) as a new biomarker for PS based on bivariate phase-rectified signal averaging (BPRSA). We hypothesized that PS exerts lasting impact on fHR. METHODS: Prospective case-control study matched for maternal age, parity, and gestational age during the third trimester using the Cohen Perceived Stress Scale (PSS-10) questionnaire with PSS-10 over or equal 19 classified as stress group (SG). Women with PSS-10 < 19 served as control group (CG). Fetal electrocardiograms were recorded by a taECG. Coupling between mHR and fHR was analyzed by BPRSA resulting in fetal stress index (FSI). Maternal hair cortisol, a memory of chronic stress exposure for 2-3 months, was measured at birth. RESULTS: 538/1500 pregnant women returned the questionnaire, 55/538 (10.2%) mother-child pairs formed SG and were matched with 55/449 (12.2%) consecutive patients as CG. Maternal hair cortisol was 86.6 (48.0-169.2) versus 53.0 (34.4-105.9) pg/mg (p = 0.029). At 36 + 5 weeks, FSI was significantly higher in fetuses of stressed mothers when compared to controls [0.43 (0.18-0.85) versus 0.00 (- 0.49-0.18), p < 0.001]. CONCLUSION: Prenatal maternal stress affects the coupling between maternal and fetal heart rate detectable non-invasively a month prior to birth. Lasting effects on neurodevelopment of affected offspring should be studied. TRIAL REGISTRATION: Clinical trial registration: NCT03389178.

Comparative proteomics reveals unexpected quantitative phosphorylation differences linked to platelet activation state.

There is a need to assess platelet activation in patients with thrombotic disorders. P-selectin and activated integrin αIIbß3 are usually quantified by flow cytometry to measure platelet activation. Monitoring changes in vasodilator-stimulated phosphoprotein (VASP) phosphorylation is an established method to determine the platelet-reactivity status. To study disruptions of platelet reactivity more comprehensively, we compared the human non-secretory platelet proteome after in-vitro -activation and -inhibition with their respective untreated controls using unbiased fluorescence two-dimensional differential in-gel electrophoresis. The non-secretory platelet proteome was more severely affected during inhibition than during activation. Strikingly, while VASP reached a 1.3-fold increase in phosphorylation levels in inhibited platelets, other protein kinase A targets showed several-fold stronger inhibition-induced phosphorylation levels, including LIM and SH3 domain protein 1 (6.7-fold), Src kinase-associated phosphoprotein 2 (4.6-fold), and Ras-related protein Rap1b (4.1-fold). Moreover, phosphorylation of integrin-linked protein kinase (ILK) and pleckstrin (PLEK) species was associated with P-selectin surface expression. The discrimination power between activation and inhibition was more pronounced for dephosphorylated ILK (3.79 Cohen's d effect size) and phosphorylated PLEK (3.77) species than for P-selectin (2.35). These data reveal new insights into the quantitative changes of the platelet reactivity proteome and suggest powerful alternatives to characterise their activation and inactivation potential.

Efficacy and safety of two post-operative drains: results of a prospectively randomized clinical study in breast cancer patients after breast conserving surgery.

OBJECTIVE: To compare the efficacy and safety of two post-operative drains in breast cancer patients after breast conserving surgery. METHODS: This was a prospectively randomized comparative study of two drains investigated in breast cancer patients after breast conserving therapy. The Redon drain ends in a tip with 28 double perforations while the Quadrain drain features 4 flexible flaps of about 0.15 m length. The drains cost 0.28 € and 3.54 €, respectively. Primary target parameter was the duration of the drains staying in the surgical site. Secondary target parameters were pain post-surgery, seroma volume, final cosmetic result and surgical site infections. RESULTS: A total of 88 patients were randomized, 47 and 41 received the Redon drain and the Quadrain drain, respectively. The mean duration of the drains staying in the surgical site was not different between the Redon and the Quadrain drain, 42.6 h (± 25.8 h) and 50.1 h (± 28.5 h), respectively (p = 0.1959). The post-operative pain score, seroma size, cosmetic result and surgical site infections were not different for both systems. CONCLUSION: The Redon drain and the new Quadrain drain were not significantly different with respect to duration in the surgical site, post-operative pain, seroma volume and cosmetic result.

Ultrasound-guided vascular access in critical illness.

Over the past two decades, ultrasound (US) has become widely accepted to guide safe and accurate insertion of vascular devices in critically ill patients. We emphasize central venous catheter insertion, given its broad application in critically ill patients, but also review the use of US for accessing peripheral veins, arteries, the medullary canal, and vessels for institution of extracorporeal life support. To ensure procedural safety and high cannulation success rates we recommend using a systematic protocolized approach for US-guided vascular access in elective clinical situations. A standardized approach minimizes variability in clinical practice, provides a framework for education and training, facilitates implementation, and enables quality analysis. This review will address the state of US-guided vascular access, including current practice and future directions.

Diagnostic workup, etiologies and management of acute right ventricle failure : A state-of-the-art paper.

INTRODUCTION: This is a state-of-the-art article of the diagnostic process, etiologies and management of acute right ventricular (RV) failure in critically ill patients. It is based on a large review of previously published articles in the field, as well as the expertise of the authors. RESULTS: The authors propose the ten key points and directions for future research in the field. RV failure (RVF) is frequent in the ICU, magnified by the frequent need for positive pressure ventilation. While no universal definition of RVF is accepted, we propose that RVF may be defined as a state in which the right ventricle is unable to meet the demands for blood flow without excessive use of the Frank-Starling mechanism (i.e. increase in stroke volume associated with increased preload). Both echocardiography and hemodynamic monitoring play a central role in the evaluation of RVF in the ICU. Management of RVF includes treatment of the causes, respiratory optimization and hemodynamic support. The administration of fluids is potentially deleterious and unlikely to lead to improvement in cardiac output in the majority of cases. Vasopressors are needed in the setting of shock to restore the systemic pressure and avoid RV ischemia; inotropic drug or inodilator therapies may also be needed. In the most severe cases, recent mechanical circulatory support devices are proposed to unload the RV and improve organ perfusion CONCLUSION: RV function evaluation is key in the critically-ill patients for hemodynamic management, as fluid optimization, vasopressor strategy and respiratory support. RV failure may be diagnosed by the association of different devices and parameters, while echocardiography is crucial.

Rare compound heterozygous variants in PNKP identified by whole exome sequencing in a German patient with ataxia-oculomotor apraxia 4 and pilocytic astrocytoma.

Ataxia-oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurologic disorder. The phenotype is characterized by ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. AOA4 is caused by biallelic pathogenic variants in the PNKP gene encoding a polynucleotide kinase 3'-phosphatase with an important function in DNA-damage repair. By whole exome sequencing, we identified 2 variants within the PNKP gene in a 27-year-old German woman with a clinical AOA phenotype combined with a cerebellar pilocytic astrocytoma diagnosed at 23 years of age. One variant, a duplication in exon 14 resulting in the frameshift c.1253_1269dup p.(Thr424fs*49), has previously been described as pathogenic, for example, in cases of AOA4. The second variant, representing a nonsense mutation in exon 17, c.1545C>G p.(Tyr515*), has not yet been described and is predicted to cause a loss of the 7 C-terminal amino acids. This is the first description of AOA4 in a patient with central European descent. Furthermore, the occurrence of a pilocytic astrocytoma has not been described before in an AOA4 patient. Our data demonstrate compound heterozygous PNKP germline variants in a German patient with AOA4 and provide evidence for a possible link with tumor predisposition. Localization of the 2 variants in human PNKP NP_009185.2. NM_007254.3:c.1253_1269dup p.(Thr424fs*49) is predicted to cause a frameshift within the kinase domain, NM_007254.3:c.1545C>G p.(Tyr515*) is predicted to cause loss of 2 C-terminal amino acids of the kinase domain and 5 additional C-terminal amino acids.

Influence of gestational diabetes on fetal autonomic nervous system: a study using phase-rectified signal-averaging analysis.

OBJECTIVES: Maternal gestational diabetes mellitus (GDM) is known to influence fetal physiology. Phase-rectified signal averaging (PRSA) is an innovative signal-processing technique that can be used to investigate fetal heart signals. The PRSA-calculated variables average acceleration capacity (AAC) and average deceleration capacity (ADC) are established indices of autonomic nervous system (ANS) function. The aim of this study was to evaluate the influence of GDM on the fetal cardiovascular and ANS function in human pregnancy using PRSA. METHODS: This was a prospective clinical case-control study of 58 mothers with diagnosed GDM and 58 gestational-age matched healthy controls in the third trimester of pregnancy. Fetal cardiotocography (CTG) recordings were performed in all cases at entry to the study, and a follow-up recording was performed in 19 GDM cases close to delivery. The AAC and ADC indices were calculated by the PRSA method and fetal heart rate short-term variation (STV) by CTG software according to Dawes-Redman criteria. RESULTS: Mean gestational age of both groups at study entry was 35.7 weeks. There was a significant difference in mean AAC (1.97 ± 0.33 bpm vs 2.42 ± 0.57 bpm; P < 0.001) and ADC (1.94 ± 0.32 bpm vs 2.28 ± 0.46 bpm; P < 0.001) between controls and fetuses of diabetic mothers. This difference could not be demonstrated using standard computerized fetal CTG analysis of STV (controls, 10.8 ± 3.0 ms vs GDM group, 11.3 ± 2.5 ms; P = 0.32). Longitudinal fetal heart rate measurements in a subgroup of women with diabetes were not significantly different from those at study entry. CONCLUSIONS: Our findings show increased ANS activity in fetuses of diabetic mothers in late gestation. Analysis of human fetal cardiovascular and ANS function by PRSA may offer improved surveillance over conventional techniques linking GDM pregnancy to future cardiovascular dysfunction in the offspring. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Risk prediction in post-infarction patients with moderately reduced left ventricular ejection fraction by combined assessment of the sympathetic and vagal cardiac autonomic nervous system.

AIM: Most deaths after myocardial infarction (MI) occur in patients with normal or moderately reduced left ventricular ejection fraction (LVEF >35%). Periodic repolarization dynamics (PRD) and deceleration capacity (DC) are novel ECG-based markers related to sympathetic and vagal cardiac autonomic nervous system activity. Here, we test the combination of PRD and DC to predict risk in post-infarction patients with LVEF >35%. METHODS AND RESULTS: We included 823 survivors of acute MI with LVEF >35%, aged ≤80years and in sinus rhythm. PRD and DC were obtained from 30-min ECG-recordings within the second week after index infarction and dichotomized at established cut-off values of ≥5.75deg2 and ≤2.5ms, respectively. Patients were classified as having normal (CAF 0), partly abnormal (DC or PRD abnormal; CAF 1) or abnormal cardiac autonomic function (DC and PRD abnormal; CAF 2). Primary endpoint was 5-year all-cause mortality. Within the first 5years of follow-up, 51 patients died (6.2%). PRD and DC effectively stratified patients into low-risk (CAF 0; n=562), intermediate-risk (CAF 1; n=193) and high-risk patients (CAF 2; n=68) with cumulative 5-year mortality rates of 2.9%, 9.4% and 25.2%, respectively (p<0.001). On multivariable analyses, CAF was independent from established risk factors (GRACE-score, diabetes mellitus, mean heart rate, heart rate variability). Addition of CAF significantly improved the model (increase of C-statistics from 0.732 (0.651-0.812) to 0.777 (0.703-0.850), p=0.047; continuous NRI (0.400, 95% CI 0.230-0.560, p<0.001); IDI (0.056, 95% CI 0.022-0.122, p<0.001)). CONCLUSION: CAF identifies new high-risk post-MI patients with LVEF >35% which might benefit from prophylactic strategies.

The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice.

Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease. Systemic administration of JQ1 elicited a hippocampal gene expression program that is associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.

Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters.

BACKGROUND: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. PATIENTS AND METHODS: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. RESULTS: We demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of ß-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of ß-catenin. Analysis of all patients with activating Wnt/ß-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion. CONCLUSIONS: The PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/ß-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. CLINICAL TRIALS.GOV IDENTIFIER: NCT02022371.

[Acute and chronic heart failure]. / Akute und chronische Herzinsuffizienz.

The initial therapy of chronic heart failure is still based on diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and in specific cases mineralocorticoid receptor antagonists. The new European Society of Cardiology (ESC) guidelines published in 2016 introduced angiotensin-receptor-neprilysin inhibitors, such as sacubitril/valsartan (LCZ 696) as new therapeutic agents in patients with chronic and progressive heart failure. New subgroup analyses for LCZ 696 have been published showing a beneficial effect in the context of various comorbidities, such as renal insufficiency, diabetes and hypotension. Furthermore, new data are available on intravenous iron substitution in chronic heart failure and on the indications for implantable converter defibrillators, cardiac resynchronization therapy and other cardiac devices. Medicinal therapy of acute heart failure is still limited. For patients who cannot be treated with medicinal therapy, mechanical circulatory support, such as extracorporeal membrane oxygenation (ECMO) should be recommended.

Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing.

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.