Early Initiation of Sacubitril/Valsartan in Patients With Acute Heart Failure and Renal Dysfunction: An Analysis of the TRANSITION Study.

BACKGROUND: Treatment of patients with heart failure with reduced ejection fraction (HFrEF) and renal dysfunction (RD) is challenging owing to the risk of further deterioration in renal function, especially after acute decompensated HF (ADHF). METHODS AND RESULTS: We assessed the effect of RD (estimated glomerular filtration rate of ≥30 to <60 mL/min/1.73 m2) on initiation, up-titration, and tolerability of sacubitril/valsartan in hemodynamically stabilized patients with HFrEF admitted for ADHF (RD, n = 476; non-RD, n = 483). At week 10, the target dose of sacubitril/valsartan (97/103 mg twice daily) was achieved by 42% patients in RD subgroup vs 54% in non-RD patients (P < .001). Sacubitril/valsartan was associated with greater estimated glomerular filtration rate improvements in RD subgroup than non-RD (change from baseline least squares mean 4.1 mL/min/1.73 m2, 95% confidence interval 2.2-6.1, P < .001). Cardiac biomarkers improved significantly in both subgroups; however, compared with the RD subgroup, the improvement was greater in those without RD (N-terminal pro-brain natriuretic peptide, -28.6% vs -44.8%, high-sensitivity troponin T -20.3% vs -33.9%) (P < .001). Patients in the RD subgroup compared with those without RD experienced higher rates of hyperkalemia (16.3% vs 6.5%, P < .001), investigator-reported cardiac failure (9.7% vs 5.6%, P = .029), and renal impairment (6.4% vs 2.1%, P = .002). CONCLUSIONS: Most patients with HFrEF and concomitant RD hospitalized for ADHF tolerated early initiation of sacubitril/valsartan and showed significant improvements in estimated glomerular filtration rate and cardiac biomarkers. CLINICAL TRIAL REGISTRATION: NCT02661217.

Development and validation of a model to predict ceiling of care in COVID-19 hospitalized patients.

BACKGROUND: Therapeutic ceiling of care is the maximum level of care deemed appropiate to offer to a patient based on their clinical profile and therefore their potential to derive benefit, within the context of the availability of resources. To our knowledge, there are no models to predict ceiling of care decisions in COVID-19 patients or other acute illnesses. We aimed to develop and validate a clinical prediction model to predict ceiling of care decisions using information readily available at the point of hospital admission. METHODS: We studied a cohort of adult COVID-19 patients who were hospitalized in 5 centres of Catalonia between 2020 and 2021. All patients had microbiologically proven SARS-CoV-2 infection at the time of hospitalization. Their therapeutic ceiling of care was assessed at hospital admission. Comorbidities collected at hospital admission, age and sex were considered as potential factors for predicting ceiling of care. A logistic regression model was used to predict the ceiling of care. The final model was validated internally and externally using a cohort obtained from the Leeds Teaching Hospitals NHS Trust. The TRIPOD Checklist for Prediction Model Development and Validation from the EQUATOR Network has been followed to report the model. RESULTS: A total of 5813 patients were included in the development cohort, of whom 31.5% were assigned a ceiling of care at the point of hospital admission. A model including age, COVID-19 wave, chronic kidney disease, dementia, dyslipidaemia, heart failure, metastasis, peripheral vascular disease, chronic obstructive pulmonary disease, and stroke or transient ischaemic attack had excellent discrimination and calibration. Subgroup analysis by sex, age group, and relevant comorbidities showed excellent figures for calibration and discrimination. External validation on the Leeds Teaching Hospitals cohort also showed good performance. CONCLUSIONS: Ceiling of care can be predicted with great accuracy from a patient's clinical information available at the point of hospital admission. Cohorts without information on ceiling of care could use our model to estimate the probability of ceiling of care. In future pandemics, during emergency situations or when dealing with frail patients, where time-sensitive decisions about the use of life-prolonging treatments are required, this model, combined with clinical expertise, could be valuable. However, future work is needed to evaluate the use of this prediction tool outside COVID-19.

Laboratory Setup for Scanning-Free Grazing Emission X-ray Fluorescence.

Grazing incidence and grazing emission X-ray fluorescence spectroscopy (GI/GE-XRF) are techniques that enable nondestructive, quantitative analysis of elemental depth profiles with a resolution in the nanometer regime. A laboratory setup for soft X-ray GEXRF measurements is presented. Reasonable measurement times could be achieved by combining a highly brilliant laser produced plasma (LPP) source with a scanning-free GEXRF setup, providing a large solid angle of detection. The detector, a pnCCD, was operated in a single photon counting mode in order to utilize its energy dispersive properties. GEXRF profiles of the Ni-Lα,ß line of a nickel-carbon multilayer sample, which displays a lateral (bi)layer thickness gradient, were recorded at several positions. Simulations of theoretical profiles predicted a prominent intensity minimum at grazing emission angles between 5° and 12°, depending strongly on the bilayer thickness of the sample. This information was used to retrieve the bilayer thickness gradient. The results are in good agreement with values obtained by X-ray reflectometry, conventional X-ray fluorescence and transmission electron microscopy measurements and serve as proof-of-principle for the realized GEXRF setup. The presented work demonstrates the potential of nanometer resolved elemental depth profiling in the soft X-ray range with a laboratory source, opening, for example, the possibility of in-line or even in situ process control in semiconductor industry.

Differences in Hip Muscle Strength and Static Balance in Patients with Transfemoral Amputations Classified at Different K-Levels: A Preliminary Cross-Sectional Study.

BACKGROUND: Following amputation, patients with lower limb amputations (LLA) are classified into different functional mobility levels (K-levels) ranging from K0 (lowest) to K4 (highest). However, K-level classification is often based on subjective criteria. Objective measures that are able to differentiate between K-levels can help to enhance the objectivity of K-level classification. OBJECTIVES: The goal of this preliminary cross-sectional study was to investigate whether differences in hip muscle strength and balance parameters exist among patients with transfemoral amputations (TFA) assigned to different K-levels. METHODOLOGY: Twenty-two participants with unilateral TFA were recruited for this study, with four participants assigned to K1 or K2, six assigned to K3 and twelve assigned to K4. Maximum isometric hip strength of the residual limb was assessed in hip flexion, abduction, extension, and adduction using a custom-made diagnostic device. Static balance was investigated in the bipedal stance on a force plate in eyes open (EO) and eyes closed (EC) conditions. Kruskal-Wallis tests were used to evaluate differences between K-level groups. FINDINGS: Statistical analyses revealed no significant differences in the parameters between the three K-level groups (p>0.05). Descriptive analysis showed that all hip strength parameters differed among K-level groups showing an increase in maximum hip torque from K1/2-classified participants to those classified as K4. Group differences were also present in all balance parameters. Increased sway was observed in the K1/2 group compared to the K4 group, especially for the EC condition. CONCLUSION: Although not statistically significant, the magnitude of the differences indicates a distinction between K-level groups. These results suggest that residual limb strength and balance parameters may have the potential to be used as objective measures to assist K-level assignment for patients with TFA. This potential needs to be confirmed in future studies with a larger number of participants.

[Dynamic vision of sportsmen with different requirement profiles for the visual apparatus]. / Dynamisches Sehen von Sportlern mit unterschiedlichem Anforderungsprofil an den visuellen Apparat.

AIM OF STUDY: In particular, in the quick ball and racket games a good dynamic seeing is required . The afferent dynamic seeing occurs via the retiina which mediates the stimuli for efferent dynamic seeing . The aim of this study was to examine the dynamic visual acuity of sportsmen from sports with different demands on their dynamic seeing (DS). METHODS: 19 sports students took part in the study. 10 subjects participated in coached team sports (group I) and 9 remaining performed individual sports (group II). The DS was assessed by means of the Düsseldorfer test for dynamic seeing of Wist which was performed twice on one day. RESULTS: The DS of the two groups in the first study did not differ (right eye 95.7 ± 10.6 % in group I vs. 94.3 ± 6.9 % in group II and left eye 97.6 ± 4.8 % vs. 95.3 ± 5.6 %; p ≥ 0.05). Also the second study there was no different in DS for the two groups (right eye 98.3 ± 2.6 % vs. 93.8 ± 8.0 % and left eye 99.3 ± 1.2 % vs. 95.6 ± 7.0 %; p ≥ 0.05). DISCUSSION: Our hypothesis about a different DS in players of ball games compared with non-ball sport players could not be proved. It is to be critically noted that a generalization is not possible due to the small sample numbers. Because DS is a necessary precondition in ball games further studies should be concentrated on its trainability.

Spatial orientation in virtual environment compared to real-world.

Virtual reality (VR) is popular across many disciplines and has been increasingly used in sports as a training tool lately. However, it is not clear whether the spatial orientation of humans works equally within VR and in the real-world. In this paper, two studies are presented, in which natural body movements were allowed and demanded. Firstly, a series of verbal and walking distance estimation tests were conducted in both the virtual and the real environment. The non-parametric Friedman test with pairwise comparisons showed no significant differences neither in verbal nor in walking distance estimations between the conditions (all p > 0.05). However, shorter distances (0.9-1.5 m) were estimated more precisely than larger distances (2.6-2.8 m) in both environments. Secondly, a self-developed route recall test to examine the spatial orientation was performed in the virtual and the real environment. The participants visually perceived the predefined route and were instructed to follow these routes with their eyes blindfolded and afterward to return to their starting position. Between the ending and the starting position, no difference between the two environments was observed (p > 0.05). Based on these two studies, the performance of the human spatial orientation preliminarily verified the same in a virtual and real environment.

Electron bunch length measurements from laser-accelerated electrons using single-shot THz time-domain interferometry.

Laser-plasma wakefield-based electron accelerators are expected to deliver ultrashort electron bunches with unprecedented peak currents. However, their actual pulse duration has never been directly measured in a single-shot experiment. We present measurements of the ultrashort duration of such electron bunches by means of THz time-domain interferometry. With data obtained using a 0.5 J, 45 fs, 800 nm laser and a ZnTe-based electro-optical setup, we demonstrate the duration of laser-accelerated, quasimonoenergetic electron bunches [best fit of 32 fs (FWHM) with a 90% upper confidence level of 38 fs] to be shorter than the drive laser pulse, but similar to the plasma period.

Direct observation of attosecond light bunching.

Temporal probing of a number of fundamental dynamical processes requires intense pulses at femtosecond or even attosecond (1 as = 10(-18) s) timescales. A frequency 'comb' of extreme-ultraviolet odd harmonics can easily be generated in the interaction of subpicosecond laser pulses with rare gases: if the spectral components within this comb possess an appropriate phase relationship to one another, their Fourier synthesis results in an attosecond pulse train. Laser pulses spanning many optical cycles have been used for the production of such light bunching, but in the limit of few-cycle pulses the same process produces isolated attosecond bursts. If these bursts are intense enough to induce a nonlinear process in a target system, they can be used for subfemtosecond pump-probe studies of ultrafast processes. To date, all methods for the quantitative investigation of attosecond light localization and ultrafast dynamics rely on modelling of the cross-correlation process between the extreme-ultraviolet pulses and the fundamental laser field used in their generation. Here we report the direct determination of the temporal characteristics of pulses in the subfemtosecond regime, by measuring the second-order autocorrelation trace of a train of attosecond pulses. The method exhibits distinct capabilities for the characterization and utilization of attosecond pulses for a host of applications in attoscience.

The role of cardiopulmonary exercise testing and echocardiography prior to elective endovascular aneurysm repair.

INTRODUCTION: Cardiopulmonary exercise testing (CPET) and transthoracic echocardiography (TTE) are common preparative investigations prior to elective endovascular aneurysm repair (EVAR). Whether these investigations can predict survival following EVAR and contribute to shared decision making is unknown. METHODS: Patients who underwent EVAR at a tertiary centre between June 2007 and December 2014 were identified from the National Vascular Registry. Variables obtained from preoperative investigations were assessed for their association with survival at three years. Regression analysis was used to determine variables that independently predicted survival at three years. RESULTS: A total of 199 patients underwent EVAR during the study period. Of these, 120 had preoperative CPET and 123 had TTE. Lower forced expiratory ventilation (FEV1), ratio of FEV1 to forced vital capacity, work at peak oxygen consumption and higher ventilatory equivalent for carbon dioxide were associated with increased mortality. Variables obtained from TTE were not associated with survival at three years although there was a low incidence of left ventricular systolic dysfunction and significant valvular disease in this cohort. CONCLUSIONS: CPET might be a useful adjunct to assist in shared decision making in patients undergoing elective EVAR and may influence anaesthetic technique. TTE does not appear to be able to discriminate between high and low risk individuals. However, a low rate of significant ventricular dysfunction and valvular disease in patients undergoing elective EVAR may account for these findings.

Despite IFN-lambda receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines.

Interferon (IFN)-lambda1, -2 and -3 (also designated as interleukin (IL)-29, IL-28alpha and IL-28beta) represent a new subfamily within the class II cytokine family. They show type I IFN-like antiviral and cytostatic activities in affected cells forming the basis for IFN-lambda1 therapy currently under development for hepatitis C infection. However, many aspects of IFN-lambdas are still unknown. This study aimed at identifying the target cells of IFN-lambdas within the immune system and the skin. Among skin cell populations, keratinocytes and melanocytes, but not fibroblasts, endothelial cells or subcutaneous adipocytes turned out to be targets. In contrast to these target cells, blood immune cell populations did not clearly respond to even high concentrations of these cytokines, despite an IFN-lambda receptor expression. Interestingly, immune cells expressed high levels of a short IFN-lambda receptor splice variant (sIFN-lambdaR1/sIL-28R1). Its characterization revealed a secreted, glycosylated protein that binds IFN-lambda1 with a moderate affinity (K(D) 73 nM) and was able to inhibit IFN-lambda1 effects. Our study suggests that IFN-lambda therapy should be suited for patients with verrucae, melanomas and non-melanoma skin cancers, apart from patients with viral hepatitis, and would not be accompanied by immune-mediated complications known from type I IFN application.

[Thoracic actinomycosis: diagnostic pitfalls and therapeutic considerations]. / Thorakale Aktinomykose: diagnostische Schwierigkeiten und therapeutische Uberlegungen.

We report two patients admitted to our hospital suspected to suffer from cancer in the lung or mediastinum, respectively. Both patients had a diagnosis of thoracic actinomycosis. A 76 year old man revealed pulmonary and endobronchial actinomycosis associated with broncholithiasis. Diagnosis was achieved by bronchoscopy. Therapy with ampicillin/sulbactam was successful. A 36 year old patient presented with bilateral pleural effusions, extended pericardial, mediastinal and pulmonary actinomycosis with pericarditis constrictiva and superior vena cava syndrome. Diagnosis was finally made by cardiac surgery with therapeutic pericardectomy. Prolonged therapy with ampicillin/sulbactam was administered with satisfactory result. Here we discuss the importance to include actinomycosis in the differential diagnosis of pulmonary affections and mediastinal masses in order to avoid diagnostic errors and to limit invasive procedures to the necessary amount. We illustrate the need of an individualized treatment approach.

Bacteria-laden microgels as autonomous three-dimensional environments for stem cell engineering.

A one-step microfluidic system is developed in this study which enables the encapsulation of stem cells and genetically engineered non-pathogenic bacteria into a so-called three-dimensional (3D) pearl lace-like microgel of alginate with high level of monodispersity and cell viability. The alginate-based microgel constitutes living materials that control stem cell differentiation in either an autonomous or heteronomous manner. The bacteria (Lactococcus lactis) encapsulated within the construct surface display adhesion fragments (III7-10 fragment of human fibronectin) for integrin binding while secreting growth factors (recombinant human bone morphogenetic protein-2) to induce osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. We concentrate on interlinked pearl lace microgels that enabled us to prototype a low-cost 3D bioprinting platform with highly tunable properties.

Reliability and performance-dependent variations of muscle function variables during isometric knee extension.

Despite the common use of standardised methods analysing neuromuscular function during knee extension, there is a lack of test-retest reliability studies. Furthermore, for most of the investigated variables it is unknown which changes of values indicate an enhancement of performance. The aim of the present study was to investigate performance-dependent variations of muscle functions during isometric contraction of knee extensors and to examine test-retest reliability of their measurement methods. For test-retest reliability sports students completed three test sessions. Highly skilled athletes, sports students and untrained subjects were investigated to determine the performance-dependent variations. The following variables were analysed: maximal voluntary contraction (MVC), voluntary activation (VA), absolute muscle reaction time (AR), muscle endurance (ME), and EMG frequency analysis (MF) of m. vastus lateralis (VL), m. vastus medialis (VM) and m. rectus femoris (RF). RESULTS TEST-RETEST-RELIABILITY: A high reliability between session 1 vs. 2 and session 2 vs. 3 was shown for MVC (ICC=0.92 and .97), VA (0.92/0.95) and ME (0.87/0.95). ICC in AR (0.23) was low between the first and second session and moderate between the second and third session (0.74). MF of VL, VM and RF showed low ICC between sessions. PERFORMANCE DEPENDENT VARIATIONS: Significant differences in nearly all variables (except VA) were found between trained (athletes and sports students) and untrained subjects.

Detection of adverse events in a Scottish hospital using a consensus-based methodology.

OBJECTIVE: To determine, using a consensus based methodology, the rate and nature of adverse events (AEs) among patients admitted to acute medicine, acute surgery and obstetrics in a large teaching hospital in Scotland. METHODS: Retrospective case-note review of 450 medical, nursing and medication records to identify and classify adverse events. For 354 patients whose length of stay was greater than 24 hours, the overall adverse event rate was 7.9% which ranged from 0% in obstetrics, 7.2% in acute medicine to 13% in acute surgery. Among all AEs, 43% were deemed preventable by a consensus group and 59% of the AEs contributed to a proportion of the patients' hospital stay or led to hospital readmission. Whilst nurse identification of adverse events was highly specific (94%), its sensitivity was poor (43%). Only 10% of the identified AEs were identified by the hospital's voluntary reporting system for adverse events. The estimated additional cost of adverse events in terms of bed days was l69,189 which if extrapolated Scotland-wide could cost l297 million per annum. CONCLUSIONS: This study supports the need to continue the traditional retrospective record review to identify adverse events. The current hospital-based reporting of adverse events does not provide a complete measure of adverse events and needs to be complemented by other measures.

[Bullectomy as emergency intervention in a mechanically ventilated patient with refractory type II respiratory failure due to chronic obstructive lung disease (COPD)]. / Erfolgreiche Notfall-Bullektomie bei einer invasiv beatmeten Patientin mit refraktärer ventilatorischer Insuffizienz im Rahmen einer akuten Exazerbation einer chronisch-obstruktiven Lungenerkrankung (COPD).

A 44-year-old female patient presented with an extensive exacerbation of severe chronic obstructive lung disease (COPD) and bullous emphysema. Because of a severe type II respiratory failure, the patient was intubated and mechanically ventilated. Respiratory failure was refractory despite appropriate ventilation regimes and pCO2 values ranged from 110 mm Hg to 180 mm Hg. Chest radiography revealed hyperinflation of two giant bullae with mediastinal shifting to the left lung. We describe a successful rescue bullectomy.

Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis.

CD44 is a transmembrane molecule appearing in numerous isoforms generated by insertions of alternatively spliced variant exons (CD44v) and having various binding partners. CD44v7 on T cells was proposed to promote colitis by preventing T-cell apoptosis. Here we demonstrate that Cd44v7-deficient T cells - like Cd44 wild-type (Cd44WT) T cells - provoked disease in two different colitis models: the model induced by CD4+CD45RBhigh T-cell transfer into Rag2-deficient mice and a new model based on ovalbumin (OVA)-specific T-cell transfer into Rag-sufficient, OVA-challenged mice. In contrast, CD44v7 absence on macrophages in recipient mice prevented colitis. Prevention was associated with the downregulation of signal transducer and activator of transcription 3 (STAT3)-activating and Foxp3-counteracting interleukin-6 (IL-6), lower numbers of phospho-STAT3-containing lymphocytes, and higher Foxp3+ T-cell counts in the colon. Consequently, the protected colons showed lower IL-12, IL-1ß expression, and decreased interferon-γ levels. Importantly, stimulation of T cells by Cd44v7-deficient macrophages induced upregulation of Foxp3 in vitro, while cotransfer of Cd44WT macrophages into Cd44v7-deficient mice reduced Foxp3+ T-cell counts and caused colitis. Accordingly, the CD44v7 ligand osteopontin, whose levels were elevated in Crohn's disease, specifically induced IL-6 in human monocytes, a cytokine also increased in these patients. We suggest macrophage-specific targeting of the CD44v7 pathway as a novel therapeutic option for Crohn's disease.

Multistep loading of titania nanoparticles in the mesopores of SBA-15 for enhanced photocatalytic activity.

A multistep deposition of anatase nanoparticles was employed to incorporate high amounts of titania into the mesopores of SBA-15. Anatase nanoparticles were synthesized and deposited following the Acid Catalyzed Sol Gel method. With this method, the size of the anatase nanoparticles can be controlled and therefore, the titania loading into the mesopores of SBA-15 can be controlled. Through multistep deposition of anatase nanoparticles, a further increase of titania loading into the mesoporous channels can be obtained. For the degradation of Rhodamine-6G, the samples synthesized by multistep deposition showed an enhanced photocatalytic activity.

Birth plans and health facility based delivery in rural Uganda.

OBJECTIVES: To evaluate whether the completion of birth plans is associated with delivery in a health facility and the perceptual causes of birth plan completion and health facility based delivery were explored according to a well-tested health behaviour theory. DESIGN: A community survey. SETTING: Rakai and Luwero districts. SUBJECTS: A total of 415 (202 in Rakai and 213 in Luwero district) respondents were randomly selected and interviewed using a mixed survey questionnaire composed of open and close-ended questions. MAIN OUTCOME MEASURES: Health facility based delivery. RESULTS: The results demonstrate a statistically significant relationship between the completion of birth plans and delivery in a health facility (OR = 1.86, 95% CI =1.1, 3.1). The fear of consequences of delivering at home was found to be an important driving force in promoting the completion of birth plans, thereby indirectly influencing the likelihood of delivery in a health facility. CONCLUSION: Given the empirical evidence presented here, this study suggests that birth plans are an important tool in improving the rate of health facility based deliveries and thus essential in the fight against maternal mortality in Uganda. It is further recommended that campaigns market the use of birth plans as a way to reduce uncertainty and manage fear and the unknown about pregnancy.

Individuals with inherited chromosomally integrated human herpes virus 6 (ciHHV-6) have functionally active HHV-6 specific T-cell immunity.

To evaluate the human herpes virus 6 (HHV-6) -specific immune response in individuals with chromosomally integrated HHV-6 (ciHHV-6), we measured HHV-6-antigen-specific cytokine responses (interferon-γ, interleukin-2, tumour necrosis factor-α) in T cells by flow cytometry in 12 and 16 individuals with and without ciHHV-6, respectively. All individuals with ciHHV-6 showed HHV-6-specific T cells with higher frequencies of HHV-6-specific CD8(+) cells (0.03-14.93, median 2.15% of CD8(+) cells) compared with non-ciHHV-6 (0.0-10.67, median 0.36%, p 0.026). The observed increased HHV-6-specific functionally active responses in individuals with ciHHV-6 clearly disprove speculations on immune tolerance in ciHHV-6 and indicate clinical and immunological implications of ciHHV-6.

Chronic heart failure and micronutrients.

Heart failure (HF) is associated with weight loss, and cachexia is a well-recognized complication. Patients have an increased risk of osteoporosis and lose muscle bulk early in the course of the disease. Basal metabolic rate is increased in HF, but general malnutrition may play a part in the development of cachexia, particularly in an elderly population. There is evidence for a possible role for micronutrient deficiency in HF. Selective deficiency of selenium, calcium and thiamine can directly lead to the HF syndrome. Other nutrients, particularly vitamins C and E and beta-carotene, are antioxidants and may have a protective effect on the vasculature. Vitamins B6, B12 and folate all tend to reduce levels of homocysteine, which is associated with increased oxidative stress. Carnitine, co-enzyme Q10 and creatine supplementation have resulted in improved exercise capacity in patients with HF in some studies. In this article, we review the relation between micronutrients and HF. Chronic HF is characterized by high mortality and morbidity, and research effort has centered on pharmacological management, with the successful introduction of angiotensin-converting enzyme inhibitors and beta-adrenergic antagonists into routine practice. There is sufficient evidence to support a large-scale trial of dietary micronutrient supplementation in HF.