the world wide randomized antibiotic envelope infection prevention wrap it trial long term follow up

Abstract Background The WRAP-IT trial reported a 40% reduction in major CIED infection within 12 months of the procedure with the antibacterial-eluting envelope (TYRX). Objective This report describes the longer-term (>12 months) envelope effects on infection reduction and complications. Methods All trial patients that underwent CIED replacement, upgrade, revision, or initial CRT-D implant received standard-of-care infection prophylaxis and were randomized 1:1 to receive the envelope or not. CIED infection incidence, and procedure and system-related complications were characterized through all follow-up (36 months) using Cox proportional hazard regression modeling. Results In total, 6800 patients received their intended randomized treatment (3371 envelope; 3429 control; mean follow-up 21.0±8.3 months). Major CIED-related infection occurred in 32 envelope patients and 51 control patients (KM estimate, 1.3% vs. 1.9%; HR: 0.64, 95% CI: 0.41-0.99; P=0.046). Any CIED-related infection occurred in 57 envelope patients and 84 control patients (KM estimate, 2.1% vs. 2.8%; HR: 0.69, 95% CI: 0.49-0.97; P=0.030). System- or procedure-related complications occurred in 235 envelope patients and 252 control patients (KM estimate, 8.0% vs. 8.2%; HR, 0.95, 95% CI: 0.79-1.13; P Conclusions The effects of the TYRX envelope in reducing the risk of CIED infection are sustained beyond the first year post-procedure, without increased risk of complication

Involvement of VDAC, Bax and Ceramides in the Efflux of AIF from Mitochondria during Curcumin-Induced Apoptosis

Contains fulltext : 80085.pdf (publisher's version ) (Open Access)BACKGROUND: We previously identified curcumin as a potent inducer of fibroblast apoptosis, which could be used to treat hypertrophic scar formation. Here we investigated the underlying mechanism of this process. PRINCIPAL FINDINGS: Curcumin-induced apoptosis could not be blocked by caspase-inhibitors and we could not detect any caspase-3/7 activity. Curcumin predominantly induced mitochondria-mediated ROS formation and stimulated the expression of the redox-sensitive pro-apoptotic factor p53. Inhibition of the pro-apoptotic signaling enzyme glycogen synthase kinase-3beta (GSK-3beta) blocked curcumin-induced apoptosis. Apoptosis was associated with high molecular weight DNA damage, a possible indicator of apoptosis-inducing factor (AIF) activity. Indeed, curcumin caused nuclear translocation of AIF, which could be blocked by the antioxidant N-acetyl cysteine. We next investigated how AIF is effluxed from mitochondria in more detail. The permeability transition pore complex (PTPC), of which the voltage-dependent anion channel (VDAC) is a component, could be involved since the VDAC-inhibitor DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) efficiently blocked AIF translocation. However, PTPC is not involved in AIF release since cyclosporine A, a specific inhibitor of the complex did not block apoptosis. Alternatively, the pro-apoptotic protein Bax could have formed mitochondrial channels and interacted with VDAC. Curcumin caused mitochondrial translocation of Bax, which was blocked by DIDS, suggesting a Bax-VDAC interaction. Interestingly, ceramide channels can also release apoptogenic factors from mitochondria and we found that addition of ceramide induced caspase-independent apoptosis. Surprisingly, this process could also be blocked by DIDS, suggesting the concerted action of Bax, VDAC and ceramide in the efflux of AIF from the mitochondrion. CONCLUSIONS: Curcumin-induced fibroblast apoptosis is totally caspase-independent and relies on the mitochondrial formation of ROS and the subsequent nuclear translocation of AIF, which is released from a mitochondrial pore that involves VDAC, Bax and possibly ceramides. The composition of the AIF-releasing channel seems to be much more complex than previously thought

Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca2+ fluxes in oxidative cell death

Oxidative DNA damage to cells activates poly(ADP-ribose)polymerase-1 (PARP-1) and the poly(ADP-ribose) formed is rapidly degraded to ADP-ribose by poly(ADP-ribose)glycohydrolase (PARG). Here we show that PARP-1 and PARG control extracellular Ca2+ fluxes through melastatin-like transient receptor potential 2 channels (TRPM2) in a cell death signaling pathway. TRPM2 activation accounts for essentially the entire Ca2+ influx into the cytosol, activating caspases and causing the translocation of apoptosis inducing factor (AIF) from the inner mitochondrial membrane to the nucleus followed by cell death. Abrogation of PARP-1 or PARG function disrupts these signals and reduces cell death. ADP-ribose-loading of cells induces Ca2+ fluxes in the absence of oxidative damage, suggesting that ADP-ribose is the key metabolite of the PARP-1/PARG system regulating TRPM2. We conclude that PARP-1/PARG control a cell death signal pathway that operates between five different cell compartments and communicates via three types of chemical messengers: a nucleotide, a cation, and proteins

Mathematical Modelling of Cell-Fate Decision in Response to Death Receptor Engagement

Cytokines such as TNF and FASL can trigger death or survival depending on cell lines and cellular conditions. The mechanistic details of how a cell chooses among these cell fates are still unclear. The understanding of these processes is important since they are altered in many diseases, including cancer and AIDS. Using a discrete modelling formalism, we present a mathematical model of cell fate decision recapitulating and integrating the most consistent facts extracted from the literature. This model provides a generic high-level view of the interplays between NFκB pro-survival pathway, RIP1-dependent necrosis, and the apoptosis pathway in response to death receptor-mediated signals. Wild type simulations demonstrate robust segregation of cellular responses to receptor engagement. Model simulations recapitulate documented phenotypes of protein knockdowns and enable the prediction of the effects of novel knockdowns. In silico experiments simulate the outcomes following ligand removal at different stages, and suggest experimental approaches to further validate and specialise the model for particular cell types. We also propose a reduced conceptual model implementing the logic of the decision process. This analysis gives specific predictions regarding cross-talks between the three pathways, as well as the transient role of RIP1 protein in necrosis, and confirms the phenotypes of novel perturbations. Our wild type and mutant simulations provide novel insights to restore apoptosis in defective cells. The model analysis expands our understanding of how cell fate decision is made. Moreover, our current model can be used to assess contradictory or controversial data from the literature. Ultimately, it constitutes a valuable reasoning tool to delineate novel experiments

MLH1 mediates PARP-dependent cell death in response to the methylating agent N-methyl-N-nitrosourea

Background:Methylating agents such as N-methyl-N-nitrosourea (MNU) can cause cell cycle arrest and death either via caspase-dependent apoptosis or via a poly(ADP-ribose) polymerase (PARP)-dependent form of apoptosis. We wished to investigate the possible role of MLH1 in signalling cell death through PARP.Methods:Fibroblasts are particularly dependent on a PARP-mediated cell death response to methylating agents. We used hTERT-immortalised normal human fibroblasts (WT) to generate isogenic MLH1-depleted cells, confirmed by quantitative PCR and western blotting. Drug resistance was measured by clonogenic and cell viability assays and effects on the cell cycle by cell sorting. Damage signalling was additionally investigated using immunostaining.Results:MLH1-depleted cells were more resistant to MNU, as expected. Despite having an intact G2/M checkpoint, the WT cells did not initially undergo cell cycle arrest but instead triggered cell death directly by PARP overactivation and nuclear translocation of apoptosis-inducing factor (AIF). The MLH1-depleted cells showed defects in this pathway, with decreased staining for phosphorylated H2AX, altered PARP activity and reduced AIF translocation. Inhibitors of PARP, but not of caspases, blocked AIF translocation and greatly decreased short-term cell death in both WT and MLH1-depleted cells. This MLH1-dependent response to MNU was not blocked by inhibitors of ATM/ATR or p53.Conclusion:These novel data indicate an important role for MLH1 in signalling PARP-dependent cell death in response to the methylating agent MNU

14 Examples of How LLMs Can Transform Materials Science and Chemistry: A Reflection on a Large Language Model Hackathon

Chemistry and materials science are complex. Recently, there have been great successes in addressing this complexity using data-driven or computational techniques. Yet, the necessity of input structured in very specific forms and the fact that there is an ever-growing number of tools creates usability and accessibility challenges. Coupled with the reality that much data in these disciplines is unstructured, the effectiveness of these tools is limited. Motivated by recent works that indicated that large language models (LLMs) might help address some of these issues, we organized a hackathon event on the applications of LLMs in chemistry, materials science, and beyond. This article chronicles the projects built as part of this hackathon. Participants employed LLMs for various applications, including predicting properties of molecules and materials, designing novel interfaces for tools, extracting knowledge from unstructured data, and developing new educational applications. The diverse topics and the fact that working prototypes could be generated in less than two days highlight that LLMs will profoundly impact the future of our fields. The rich collection of ideas and projects also indicates that the applications of LLMs are not limited to materials science and chemistry but offer potential benefits to a wide range of scientific disciplines

A review : a comprehensive review of soft and rigid wearable rehabilitation and assistive devices with a focus on the shoulder joint

The importance of the human upper limb role in performing daily life and personal activities is significant. Improper functioning of this organ due to neurological disorders or surgeries can greatly affect the daily activities performed by patients. This paper aims to comprehensively review soft and rigid wearable robotic devices provided for rehabilitation and assistance focusing on the shoulder joint. In the last two decades, many devices have been proposed in this regard, however, there have been a few groups whose devices have had effective therapeutic capability with acceptable clinical evidence. Also, there were not many portable, lightweight and user-friendly devices. Therefore, this comprehensive study could pave the way for achieving optimal future devices, given the growing need for these devices. According to the results, the most commonly used plan was Exoskeleton, the most commonly used actuators were electrical, and most devices were considered to be stationary and rigid. By doing these studies, the advantages and disadvantages of each method are also presented. The presented devices each have a new idea and attitude in a specific field to solve the problems of movement disorders and rehabilitation, which were in the form of prototypes, initial clinical studies and sometimes comprehensive clinical and commercial studies. These plans need more comprehensive clinical trials to become a complete and efficient plan. This article could be used by researchers to identify and evaluate the important features and strengths and weaknesses of the plans to lead to the presentation of more optimal plans in the future

An abdominal active can defibrillator may facilitate a successful generator change when a lead failure is present

Aims: Defibrillator generator changes are frequently performed on patients with an implantable cardioverter defibrillator in an abdominal pocket. These patients usually have epicardial patches or older endocardial lead systems. At the time of a defibrillator generator change defibrillation may be unsuccessful as a result of lead failure. We tested the hypothesis that an active can defibrillator implanted in the abdominal pocket could replace a non-functioning endocardial lead or epicardial patch. Methods and Results: An abdominal defibrillator generator change was performed in 10 patients, (mean age= 67 ± 13 years, nine men). Initially, a defibrillation threshold (DFT) was obtained using a passive defibrillator and the chronic endocardial or epicardial lead system. DFTs were then performed using an active can emulator and one chronic lead to simulate endocardial or epicardial lead failure. We tested 30 lead configurations (nine endocardial and 21 epicardial). Although a DFT of 7·3 ± 4·2 joules was obtained with the intact chronic lead system, the active can emulator and one endocardial or epicardial lead still yielded an acceptable DFT of 19·9 ± 6-1 joules. In addition, a successful implant (DFT ≤24 joules) could have been accomplished in 28 of 30 (93%) lead configurations. Conclusion: An active can defibrillator in an abdominal pocket may allow for a successful generator change in patients with defibrillator lead malfunction. This would be simpler than abandoning the abdominal implant and moving to a new pectoral device and lead or tunnelling a new endocardial electrode. However, loss of defibrillation capability with a particular complex lead may be a warning of impending loss of other functions (eg. sensing and/or pacing). © 1999 The European Society of Cardiology