APR Technologies (Sweden)

OBJECTIVESCardiopulmonary bypass (CPB) management may potentially play a role in the development of new-onset atrial fibrillation (AF) after cardiac surgery. The aim of this study was to explore this potential association.METHODSPatients who underwent coronary artery bypass grafting and/or valvular surgery during 2016–2020 were included in an observational single-centre study. Data collected from the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry and a local CPB database were merged. Associations between individual CPB variables (CPB and aortic clamp times, arterial and central venous pressure, mixed venous oxygen saturation, blood flow index, bladder temperature and haematocrit) and new-onset AF were analysed using multivariable logistic regression models adjusted for patient characteristics, comorbidities and surgical procedure.RESULTSOut of 1999 patients, 758 (37.9%) developed new-onset AF. Patients with new-onset postoperative AF were older, had a higher incidence of previous stroke, worse renal function and higher EuroSCORE II and CHA2DS2-VASc scores and more often underwent valve surgery. Longer CPB time [adjusted odds ratio 1.05 per 10 min (95% confidence interval 1.01–1.08); P = 0.008] and higher flow index [adjusted odds ratio 1.21 per 0.2 l/m2 (95% confidence interval 1.02–1.42); P = 0.026] were associated with an increased risk for new-onset AF, while the other variables were not. A sensitivity analysis only including patients with isolated coronary artery bypass grafting supported the primary analyses.CONCLUSIONSCPB management following current guideline recommendations appears to have minor or no influence on the risk of developing new-onset AF after cardiac surgery.

Simple SummaryProstate cancer is the most prevalent male cancer. It poses a survival risk if it spreads and fails treatment. In search of fresh insight into lethal prostate cancers, we examined failures in cancer defence systems operated by the key anticancer protein p53. Normally, levels of p53 activity are kept low by the protein MDM4, and consistently, we found that high MDM4 levels pose a prostate cancer risk in this context. Outside this explanation, we discovered that high MDM4 levels are also a cancer risk when p53 is genetically altered and unable to fight cancer, or even mutated to drive cancer spread. Our novel findings uncovered MDM4 inhibition as a new concept for prostate cancer treatment, and we demonstrated efficacy and uncovered mechanisms of action. Importantly, we showed that targeting MDM4 halted the growth of aggressive prostate cancer cells with mutant p53, and this was potentiated by a drug clinically trialled to target mutant p53 cancers.Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.

An integrated model is constructed for a Li‐ion battery module composed of cylindrical cells by coupling individual first‐order equivalent circuit models (ECMs) with a 3D heat transfer model, also considering the fluid flow dynamics of the applied cooling liquid, and bench‐marked against experimental data. This model simulates a representative unit of the battery module with direct liquid cooling in a parallel configuration. Instead of assigning specific values to the featured parameters involved in the ECMs, they are here defined as 4D arrays. This makes it possible to simultaneously consider the effect of the state of charge, current rate, and temperature on the battery dynamics, making the model more adaptive, versatile, and connectable to the battery cell electrochemistry. According to the simulation results, the model employing state‐dependent battery properties fits better with the experimental cooling results. Additionally, the temperature uniformity of the module with a parallel cooling configuration is improved compared to a serial configuration. However, the increase of the absolute core temperature cannot be directly controlled by the surface cooling due to the slow heat transport rate across the battery material. The simulations also provide directions for the modification of module design, to the potential benefit of battery pack developers.

In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1MET) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins.

Recommender systems are ubiquitous in the modern internet, where they help users find items they might like. A widely deployed recommendation approach is item-based collaborative filtering. This approach relies on analyzing large item cooccurrence matrices that denote how many users interacted with a pair of items. The potentially quadratic number of items to compare poses a scalability bottleneck in analyzing such item cooccurrences. Additionally, this problem intensifies in real world use cases with incrementally growing datasets, especially when the recommendation model is regularly recomputed from scratch. We highlight the connection between the growing cost of item-based recommendation and densification processes in common interaction datasets. Based on our findings, we propose an efficient incremental algorithm for item-based collaborative filtering based on cooccurrence analysis. This approach restricts the number of interactions to consider from 'power users' and 'ubiquitous items' to guarantee a provably constant amount of work per user-item interaction to process. We discuss efficient implementations of our algorithm on a single machine as well as on a distributed stream processing engine, and present an extensive experimental evaluation. Our results confirm the asymptotic benefits of the incremental approach. Furthermore, we find that our implementation is an order of magnitude faster than existing open source recommender libraries on many datasets, and at the same time scales to high dimensional datasets which these existing recommenders fail to process.

Wafer-level vacuum packaging is vital in the fabrication of many microelectromechanical systems (MEMS) devices and enables significant cost reduction in high-volume MEMS production. In this paper, we propose a low-temperature wafer-level vacuum packaging method based on plastic deformation and low-temperature welding of copper sealing rings with a small footprint. A device wafer with copper ring structures and a cap wafer with corresponding metalized grooves are placed inside a vacuum chamber and pressed together at a temperature of 250 °C, resulting in low-temperature welding of the copper, and thus, hermetic sealing of the cavities enclosed by the sealing rings. The vacuum pressure inside the fabricated cavities 146 days after bonding was measured using residual gas analysis to be as low as $2.6\times 10^{-2}$ mbar. Based on this value, the leak rate is calculated to be smaller than $ {3.6}\times {10}^{-16}$ mbarL/s using the most conservative assumptions, demonstrating the excellent hermeticity of the seals. Shear testing was used to demonstrate that the seals are mechanically stable with over 90 MPa in shear strength for $5.2~\mu \text{m}$ -high Cu sealing rings with widths down to $8~\mu \text{m}$ . The reported method is potentially compatible with complementary metal-oxide-semiconductor (CMOS) substrates and may be applied to vacuum packaging of 3-D heterogeneously integrated MEMS on state-of-the-art CMOS substrates. [2016-0252]

Mutant p53-carrying tumors are often more resistant to chemotherapeutical drugs. We demonstrate here that the mutant p53-reactivating compound PRIMA-1(MET) acts synergistically with several chemotherapeutic drugs to inhibit tumor cell growth. Combined treatment with cisplatin and PRIMA-1(MET) resulted in a synergistic induction of tumor cell apoptosis and inhibition of human tumor xenograft growth in vivo in SCID mice. The induction of mutant p53 levels by chemotherapeutic drugs is likely to increase the sensitivity of tumor cells to PRIMA-1(MET). Thus, the combination of PRIMA-1(MET) with currently used chemotherapeutic drugs may represent a novel and more efficient therapeutic strategy for treatment of mutant p53-carrying tumors.

The authors describe a case of transfer of an arterialized cephalic venous flap from the anteromedial arm region to the neck with the cranial limb of the cephalic vein serving as the drainage vein and a pedicle. The burn scar contracture of a 45-year-old man was released and repaired with a venous flap based on the cephalic vein in the anteromedial arm. After dissection of the cranial end of the cephalic vein as a drainage vein in the deltopectoral groove, until the flap could be transposed easily to the neck defect pedicled on the dissected cranial limb of the cephalic vein, the flap was arterialized by anastomosing the caudal end of the cephalic vein to a recipient artery in the neck The donor defect was skin grafted and the flap survived completely. The neck contracture improved substantially.