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Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin 17A, a key cytokine involved in the development of psoriasis. Secukinumab has shown long-lasting efficacy and safety in the complete spectrum of psoriatic disease, including disease localized to nails, scalp, palms and soles, and joints (peripheral and axial arthritis). Given the chronic and relapsing nature of psoriasis, long-term data might help to fully characterize the efficacy and safety profile of secukinumab as well as its impact on quality of life.
Introduction and Objectives: Surgical techniques such as preservation of the full functional-length of the urethral sphincter (FFLU) have a positive impact on postoperative continence rates. Thereby, data on very early continence rates after radical prostatectomy (RP) are scarce. The aim of the present study was to analyze very early continence rates in patients undergoing FFLU during RP.
Materials and Methods: Very early-continence was assessed by using the PAD-test within 24 h after removal of the transurethral catheter. The PAD-test is a validated test that measures the amount of involuntary urine loss while performing predefined physical activities within 1 h (e.g., coughing, walking, climbing stairs). Full continence was defined as a urine loss below 1 g. Mild, moderate, and severe incontinence was defined as urine loss of 1–10 g, 11–50 g, and >50 g, respectively.
Results: 90 patients were prospectively analyzed. Removal of the catheter was performed on the 6th postoperative day. Proportions for no, mild, moderate and severe incontinence were 18.9, 45.5, 20.0, and 15.6%, respectively. In logistic regression younger age was associated with significant better continence (HR 2.52, p = 0.04), while bilateral nerve-sparing (HR 2.56, p = 0.057) and organ-confined tumor (HR 2.22, p = 0.078) showed lower urine loss, although the effect was statistically not significant. In MVA, similar results were recorded.
Conclusion: Overall, 64.4% of patients were continent or suffered only from mild incontinence at 24 h after catheter removal. In general, reduced urine loss was recorded in younger patients, patients with organ-confined tumor and in patients with bilateral nerve sparing. Severe incontinence rates were remarkably low with 15.6%.
Multisensory integration strongly depends on the temporal proximity between two inputs. In the audio-visual domain, stimulus pairs with delays up to a few hundred milliseconds can be perceived as simultaneous and integrated into a unified percept. Previous research has shown that the size of this temporal window of integration can be narrowed by feedback-guided training on an audio-visual simultaneity judgment task. Yet, it has remained uncertain how the neural network that processes audio-visual asynchronies is affected by the training. In the present study, participants were trained on a 2-interval forced choice audio-visual simultaneity judgment task. We recorded their neural activity with magnetoencephalography in response to three different stimulus onset asynchronies (0 ms, each participant’s individual binding window, 300 ms) before, and one day following training. The Individual Window stimulus onset asynchrony condition was derived by assessing each participant’s point of subjective simultaneity. Training improved performance in both asynchronous stimulus onset conditions (300 ms, Individual Window). Furthermore, beta-band amplitude (12–30 Hz) increased from pre-compared to post-training sessions. This increase moved across central, parietal, and temporal sensors during the time window of 80–410 ms post-stimulus onset. Considering the putative role of beta oscillations in carrying feedback from higher to lower cortical areas, these findings suggest that enhanced top-down modulation of sensory processing is responsible for the improved temporal acuity after training. As beta oscillations can be assumed to also preferentially support neural communication over longer conduction delays, the widespread topography of our effect could indicate that training modulates not only processing within primary sensory cortex, but rather the communication within a large-scale network.
The current problem of increasing antibiotic resistance and the resurgence of numerous infections indicate the need for novel vaccination strategies more than ever. In vaccine development, the search for and the selection of adequate vaccine antigens is the first important step. In recent years, bacterial outer membrane proteins have become of major interest, as they are the main proteins interacting with the extracellular environment. Trimeric autotransporter adhesins (TAAs) are important virulence factors in many Gram-negative bacteria, are localised on the bacterial surface, and mediate the first adherence to host cells in the course of infection. One example is the Neisseria adhesin A (NadA), which is currently used as a subunit in a licensed vaccine against Neisseria meningitidis. Other TAAs that seem promising vaccine candidates are the Acinetobacter trimeric autotransporter (Ata), the Haemophilus influenzae adhesin (Hia), and TAAs of the genus Bartonella. Here, we review the suitability of various TAAs as vaccine candidates.
Systematic protein localization and protein-protein interaction studies to characterize specific protein functions are most effectively performed using tag-based assays. Ideally, protein tags are introduced into a gene of interest by homologous recombination to ensure expression from endogenous control elements. However, inefficient homologous recombination makes this approach difficult in mammalian cells. Although gene targeting efficiency by homologous recombination increased dramatically with the development of designer endonuclease systems such as CRISPR/Cas9 capable of inducing DNA double-strand breaks with unprecedented accuracy, the strategies still require synthesis or cloning of homology templates for every single gene. Recent developments have shown that endogenous protein tagging can be achieved efficiently in a homology independent manner. Hence, combinations between CRISPR/Cas9 and generic tag-donor plasmids have been used successfully for targeted gene modifications in mammalian cells. Here, we developed a tool kit comprising a CRISPR/Cas9 expression vector with several EGFP encoding plasmids that should enable tagging of almost every protein expressed in mammalian cells. By performing protein-protein interaction and subcellular localization studies of mTORC1 signal transduction pathway-related proteins expressed in HEK293T cells, we show that tagged proteins faithfully reflect the behavior of their native counterparts under physiological conditions.
Background & Aims: Renal function assessed by creatinine is a key prognostic factor in cirrhotic patients. However, creatinine is influenced by several factors, rendering interpretation difficult in some situations. This is especially important in early stages of renal dysfunction where renal impairment might not be accompanied by an increase in creatinine. Other parameters, such as cystatin C (CysC) and beta‐trace protein (BTP), have been evaluated to fill this gap. However, none of these studies have considered the role of the patient's sex. The present study analysed CysC and BTP to evaluate their prognostic value and differentiate them according to sex.
Patients and methods: CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt (TIPS)‐patients from the NEPTUN‐STUDY(NCT03628807) and analysed their relationship with mortality and sex. Propensity score for age, MELD, etiology and TIPS indication was used.
Results_ Cystatin C and BTP showed excellent correlations with creatinine values at baseline and follow‐up. CysC was an independent predictor of overall mortality (HR = 1.66(1.33‐2.06)) with an AUC of 0.75 and identified a cut‐off of 1.55 mg/L in the whole cohort. Interestingly, CysC was significantly lower in females, also after propensity score matching. In males, the only independent predictor was the creatinine level (HR = 1.54(1.25‐1.58)), while in females CysC levels independently predicted mortality (HR = 3.17(1.34‐7.52)).
Conclusion: This study demonstrates for the first time that in TIPS‐patients creatinine predicts mortality in males better than in females, whereas CysC is a better predictor of mortality in females. These results may influence future clinical decisions on therapeutic options for example, allocation for liver transplantation in TIPS‐patients.
Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients.
Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5–2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF).
Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “full-blown” systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes.
Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.
Background: The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age.
Material/Methods: Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years).
Results: Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus.
Conclusions: Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.
Purpose: To review the role of radiotherapy (RT) in the treatment of renal cell cancer (RCC) in the curative and palliative setting.
Content: Details related to the clinical outcomes of primary, preoperative, postoperative and palliative RT are discussed, along with a presentation of the established role of surgery and systemic therapy. An overview of data derived from mono- and multi-institutional trials is provided.
Conclusion: Radiotherapy has been shown to provide good symptom palliation and local control in RCC depending on the dose that can be delivered. There is emerging data suggesting that with the use of high-precision RT methods the indication spectrum of RT can be exploited covering different clinical situations particularly for unresectable local recurrences and oligometastatic disease.
The ecological role of bacterial seed endophytes associated with wild cabbage in the United Kingdom
(2019)
Endophytic bacteria are known for their ability in promoting plant growth and defense against biotic and abiotic stress. However, very little is known about the microbial endophytes living in the spermosphere. Here, we isolated bacteria from the seeds of five different populations of wild cabbage (Brassica oleracea L) that grow within 15 km of each other along the Dorset coast in the UK. The seeds of each plant population contained a unique microbiome. Sequencing of the 16S rRNA genes revealed that these bacteria belong to three different phyla (Actinobacteria, Firmicutes, and Proteobacteria). Isolated endophytic bacteria were grown in monocultures or mixtures and the effects of bacterial volatile organic compounds (VOCs) on the growth and development on B. oleracea and on resistance against a insect herbivore was evaluated. Our results reveal that the VOCs emitted by the endophytic bacteria had a profound effect on plant development but only a minor effect on resistance against an herbivore of B. oleracea. Plants exposed to bacterial VOCs showed faster seed germination and seedling development. Furthermore, seed endophytic bacteria exhibited activity via volatiles against the plant pathogen F. culmorum. Hence, our results illustrate the ecological importance of the bacterial seed microbiome for host plant health and development.