Dennisbagger4174

Cardiac arrhythmias impact over 12 million people globally, with an increasing incidence of acquired arrhythmias. Although animal models have shed light onto fundamental arrhythmic mechanisms, species-specific differences and ethical concerns remain. Current human models using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) either lack the higher order tissue organization of the heart or implement unreliable arrhythmia induction techniques. Our goal was to develop a robust model of acquired arrhythmia by disrupting cardiomyocyte cell-cell signaling - one of the hallmarks of complex arrhythmias. Human 3D microtissues were generated by seeding hydrogel-embedded hiPSC-CMs and cardiac fibroblasts into an established microwell system designed to enable active and passive force assessment. Cell-cell signaling was disrupted using methyl-beta cyclodextrin (MBCD), previously shown to disassemble cardiac gap junctions. We demonstrate that arrhythmias were progressive and present in all microtissuc arrhythmia-on-a-chip with high reproducibility, fidelity, and extensive functional applicability. To mimic in vivo conditions, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts from healthy controls were combined in a biocompatible fibrin hydrogel and seeded between two deflectable polymeric rods. Using the innate functional properties of this 3D model as well as advanced optical imaging techniques we demonstrated dramatic changes in contraction rate, synchronicity, and electrophysiological conduction in arrhythmic tissues relative to controls. Taken together, these data demonstrate the distinctive potential of this new model for pathophysiological studies, and for arrhythmia drug testing applications.Endothelial senescence has been identified as an early event in the development of endothelial dysfunction, a hallmark of cardiovascular disease. This study developed theranostic nanocarriers (NC) decorated with VCAM-1 antibodies (NC-VCAM-1) in order to target cell surface VCAM-1, which is overexpressed in senescent endothelial cells (ECs) for diagnostic and therapeutic purposes. Incubation of Ang II-induced premature senescent ECs or replicative senescent ECs with NC-VCAM-1 loaded with lipophilic fluorescent dyes showed higher fluorescence signals than healthy EC, which was dependent on the NC size and VCAM-1 antibodies concentration, and not observed following masking of VCAM-1. NC loaded with omega 3 polyunsaturated fatty acid (NC-EPADHA61) were more effective than native EPADHA 61 to prevent Ang II-induced VCAM-1 and p53 upregulation, and SA-β-galactosidase activity in coronary artery segments. These theranostic NC might be of interest to evaluate the extent and localization of endothelial senescence and to prevent pro-senescent endothelial responses.Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system with poor prognosis. Therapeutic drugs for RCC can easily develop resistance or have unignorable toxicity or limited efficiency. Here, the thermosensitive mitochondrial metabolism-interfering anticancer drug lonidamine (LND) was combined with the photothermal material polydopamine (PDA) to treat RCC. To delivery drugs accurately to RCC site, LND and PDA were loaded in stellate mesoporous silica nanoparticles (MSNs) with a large surface area and cloaked with RCC membranes (MLP@M). The results showed that MLP@M exhibited excellent tumor targeting ability. The synergistic effects of LND and PDA in MLP@M were greatly enhanced when triggered by an 808 nm laser. Moreover, the antiproliferative and tumor suppressing abilities were enhanced with good biocompatibility after MLP@M + laser treatment. Additionally, 80% of RCC tumor-bearing mice treated with MLP@M + laser did not relapse. Our study provides a potential therapeutic approach for RCC treatment.This work aimed to identify the lead causes of upper limb injury presenting to a busy hand and major trauma unit during the UK COVID-19 domestic lockdown period, in comparison to a cohort from the same period one year previously. Hand and upper limb injuries presenting to the host organization during a pre-lockdown period (23rd March 2019-11th May 2019) and the formal UK lockdown period (23rd March 2020-11th May 2020) were compared, using data collated from the host institution's hand surgery database. The UK lockdown period was associated with a 52% fall in the number of patients presenting to the service with hand and upper limb injuries (589 pre-lockdown vs. 284 during lockdown). There was a significant increase in the proportion of injuries due to machinery use during lockdown (38, 6.5% pre-lockdown vs. 33, 11.6% during lockdown, P = 0.009), other etiologies were consistent. The proportion requiring surgical management were similar (n = 272, 46.2% pre-lockdown vs. n = 138, 48.6% during lockdown, P = 0.50). The proportion requiring overnight admission fell (n = 94, 16.0% pre-lockdown vs. 29, 10.2% during lockdown, P = 0.022). TED347 COVID-19 related lockdown in the UK resulted in a reduction in the presenting numbers of hand related injuries; however almost half of these patients still required surgery. These data may be of use to other hand surgery centers for resource planning during future lockdown periods, and for injury prevention strategies in the post-COVID-19 world.Alcoholic fatty liver disease (AFLD) is induced by alcohol consumption and may progress to more severe liver diseases such as alcoholic steatohepatitis, fibrosis and cirrhosis, and even hepatocellular carcinoma. Mesencephalic astrocyte-derived neurotrophic factor (MANF) participates in maintaining lipid homeostasis. However, the role of MANF in the pathogenesis of AFLD remains unclear. We established an AFLD mouse model following the US National Institute on Alcohol Abuse and Alcoholism procedure. Both mRNA and protein levels of MANF were significantly increased in the chronic binge alcohol feeding model. Liver-specific knockout of MANF aggravated hepatic lipid accumulation. Similarly, liver-specific overexpression of MANF alleviated AFLD in mouse livers. MANF affected hepatic lipid metabolism by modulating autophagy. The levels of LC3-II and Atg5-Atg12 were decreased in mouse livers with MANF liver-specific knockout and increased with MANF liver-specific overexpression. Furthermore, MANF changed the phosphorylation of Stat3 and its nuclear localization. MANF may have a protective role in the development of AFLD.

Leadless intracardiac pacemakers were developed to avoid the complications of transvenous pacing systems. The Medtronic Micra™ transcatheter pacemaker is one such system. We found an unexpected number of major adverse clinical events (MACE) in the Food and Drug Administration's Manufacturers and User Facility Device Experience (MAUDE) database associated with Micra implantation.

The purpose of this study was to describe these MACE and compare them to implant procedure MACE in MAUDE for Medtronic CapSureFix™ active-fixation transvenous pacing leads.

During January 2021, we queried the MAUDE database for reports of MACE for Micra pacemakers and CapSureFix leads using the simple search terms "death," "tamponade," and "perforation." Reports from 2016-2020 were included.

The search identified 363 MACE for Micra and 960 MACE for CapSureFix leads, including 96 Micra deaths (26.4%) vs 23 CapSureFix deaths (2.4%) (P <.001); 287 Micra tamponades (79.1%) vs 225 tamponades for CapSureFix (23.4%) (P <.001); ss for implantation of CapSureFix transvenous ventricular pacing leads.Online healthcare consultation offers people a convenient way to consult doctors. In this paper, we aim at building a generative dialog system for Chinese healthcare consultation. As the original Seq2seq architecture tends to suffer the issue of generating low-quality responses, the multi-source Seq2seq architecture generating more informative responses is much more preferred in this task. The multi-source Seq2seq architecture takes advantage of retrieval techniques to obtain responses from the database, and then takes these responses alongside the user-issued question as input. However, some of the retrieved responses might be not much related to the user-issued question, resulting in the generation of unsatisfying responses that are not correct in diagnosis or instead provide inappropriate advice on prevention or treatment. Therefore, this paper proposes multi-source Seq2seq guided by knowledge (MSSGK) to handle this problem. MSSGK differs from the multi-source Seq2seq architecture in that domain knowledge, including disease labels and topic labels about prevention and treatment, is introduced into the response generation via a multi-task learning framework. To better exploit the domain knowledge, we propose three attention mechanisms to provide more appropriate guidance for response generation. Experimental results on a dataset of real-world healthcare consultation show the effectiveness of the proposed method.Decades of comparative and experimental work suggest that testosterone (T) promotes mating effort at the expense of parental effort in many vertebrates. There is abundant evidence that T-mediated trade-offs span both evolutionary and seasonal timescales, as T is often higher in species or breeding stages with greater mating competition and lower in association with parental effort. However, it is less clear whether transient elevations in T within a male's own reactive scope can affect parental effort in the same way, with effects that are visible to natural selection. Here, we injected free-living male tree swallows (Tachycineta bicolor) with gonadotropin-releasing hormone (GnRH), thus temporarily maximizing T production within an individual's own limit. Passive loggers at each nest showed that GnRH-injected males provisioned more frequently than saline males for the subsequent day, and their offspring gained more mass during that time. The degree of offspring growth was positively correlated with the father's degree of T elevation, but provisioning was not proportional to changes in T, and GnRH- and saline-injected males did not differ in corticosterone secretion. These results suggest that prior knowledge of T-mediated trade-offs garnered from seasonal, evolutionary, and experimental research cannot necessarily be generalized to the timescale of transient fluctuations in T secretion within an individual. Instead, we propose that GnRH-induced T fluctuations may not result in visible trade-offs if selection has already sculpted an individual male's reactive scope based on his ability to handle the competing demands of mating and parental care.

To compare radial peripapillary capillary (RPC) plexus vascular parameters and retinal nerve fiber layer (RNFL) thickness between those with Parkinson's disease (PD) and controls.

Prospective, cross-sectional study.

A total of 151 eyes of 81 PD participants and 514 eyes of 266 controls.

Participants underwent OCT angiography (OCTA) imaging using the Zeiss Cirrus HD-5000 AngioPlex (Carl Zeiss AG). Capillary perfusion density (CPD) and capillary flux index (CFI) were assessed using a 4.5 × 4.5-mm peripapillary scan, and RNFL thickness was assessed using a 200 × 200-μm optic nerve cube OCT scan. Hoehn and Yahr clinical staging for PD was determined by an experienced movement disorders specialist. Generalized estimating equations adjusted for age and sex were used for analysis.

Differences in RNFL thickness, CPD, and CFI as assessed using multivariable generalized estimating equations between individuals with PD and controls.

After adjustment for age and sex, average CPD (0.446% ± 0.018% vs. 0.439% ± 0.