High frequency oscillations in human memory and cognition: a neurophysiological substrate of engrams?

Despite advances in understanding the cellular and molecular processes underlying memory and cognition, and recent successful modulation of cognitive performance in brain disorders, the neurophysiological mechanisms remain underexplored. High frequency oscillations beyond the classic electroencephalogram spectrum have emerged as a potential neural correlate of fundamental cognitive processes. High frequency oscillations are detected in the human mesial temporal lobe and neocortical intracranial recordings spanning gamma/epsilon (60-150 Hz), ripple (80-250 Hz) and higher frequency ranges. Separate from other non-oscillatory activities, these brief electrophysiological oscillations of distinct duration, frequency and amplitude are thought to be generated by coordinated spiking of neuronal ensembles within volumes as small as a single cortical column. Although the exact origins, mechanisms, and physiological roles in health and disease remain elusive, they have been associated with human memory consolidation and cognitive processing. Recent studies suggest their involvement in encoding and recall of episodic memory with a possible role in the formation and reactivation of memory traces. High frequency oscillations are detected during encoding, throughout maintenance, and right before recall of remembered items, meeting a basic definition for an engram activity. The temporal coordination of high frequency oscillations reactivated across cortical and subcortical neural networks is ideally suited for integrating multimodal memory representations, which can be replayed and consolidated during states of wakefulness and sleep. High frequency oscillations have been shown to reflect coordinated bursts of neuronal assembly firing and offer a promising substrate for tracking and modulation of the hypothetical electrophysiological engram.

Retrospective study of germline variants in patients with hereditary melanoma study criteria in a real clinical practice setting.

INTRODUCTION: Five to twelve percent of melanomas show aggregation of melanomas or other related tumors within the same family or individual. Genes such as CDKN2A, or BAP1, among others, have been involved in this condition. MATERIAL AND METHODS: Retrospective descriptive study that includes patients from Cruces University Hospital (2016-2023) who met any of the following criteria: presence of two or more melanomas (1), or a melanoma and a pancreatic cancer (2) in the same individual; presence of a melanoma in an individual and one or more first- or second-degree relatives with melanoma or pancreatic cancer (3); first- or second-degree relationship with an individual with a known deleterious variant in genes related to melanoma predisposition (4); or incidental discovery of deleterious variants in genes related to predisposition to melanoma, within hereditary cancer panels carried out for reasons other than melanoma (5). RESULTS: 59 families were included (69 patients; 63.8% women), of which 8.5% (13% of patients) presented pathogenic/likely pathogenic variants (PV/LPV) in CDKN2A (6% of families and patients, excluding criteria 4 and 5), and 1.7% of families (1.4% of patients) presented PV/LPV in BAP1, BRCA2 and TERF2IP. DISCUSSION AND CONCLUSIONS: The frequencies of PV/LPV in CDKN2A are similar to those previously described. This study could contribute to the knowledge of the characteristics of patients who meet genetic study criteria for hereditary melanoma, in a setting of real clinical practice.

A Computer Vision-Based System to Help Health Professionals to Apply Tests for Fall Risk Assessment.

The increase in life expectancy, and the consequent growth of the elderly population, represents a major challenge to guarantee adequate health and social care. The proposed system aims to provide a tool that automates the evaluation of gait and balance, essential to prevent falls in older people. Through an RGB-D camera, it is possible to capture and digitally represent certain parameters that describe how users carry out certain human motions and poses. Such individual motions and poses are actually related to items included in many well-known gait and balance evaluation tests. According to that information, therapists, who would not need to be present during the execution of the exercises, evaluate the results of such tests and could issue a diagnosis by storing and analyzing the sequences provided by the developed system. The system was validated in a laboratory scenario, and subsequently a trial was carried out in a nursing home with six residents. Results demonstrate the usefulness of the proposed system and the ease of objectively evaluating the main items of clinical tests by using the parameters calculated from information acquired with the RGB-D sensor. In addition, it lays the future foundations for creating a Cloud-based platform for remote fall risk assessment and its integration with a mobile assistant robot, and for designing Artificial Intelligence models that can detect patterns and identify pathologies for enabling therapists to prevent falls in users under risk.

A Metric Based on the Efficient Determination Criterion.

This paper extends the concept of metrics based on the Bayesian information criterion (BIC), to achieve strongly consistent estimation of partition Markov models (PMMs). We introduce a set of metrics drawn from the family of model selection criteria known as efficient determination criteria (EDC). This generalization extends the range of options available in BIC for penalizing the number of model parameters. We formally specify the relationship that determines how EDC works when selecting a model based on a threshold associated with the metric. Furthermore, we improve the penalty options within EDC, identifying the penalty ln(ln(n)) as a viable choice that maintains the strongly consistent estimation of a PMM. To demonstrate the utility of these new metrics, we apply them to the modeling of three DNA sequences of dengue virus type 3, endemic in Brazil in 2023.

Helical Bilayer Nanographenes: Impact of the Helicene Length on the Structural, Electrochemical, Photophysical, and Chiroptical Properties.

Helical bilayer nanographenes (HBNGs) are chiral π-extended aromatic compounds consisting of two π-π stacked hexabenzocoronenes (HBCs) joined by a helicene, thus resembling van der Waals layered 2D materials. Herein, we compare [9]HBNG, [10]HBNG, and [11]HBNG helical bilayers endowed with [9], [10], and [11]helicenes embedded in their structure, respectively. Interestingly, the helicene length defines the overlapping degree between the two HBCs (number of benzene rings involved in π-π interactions between the two layers), being 26, 14, and 10 benzene rings, respectively, according to the X-ray analysis. Unexpectedly, the electrochemical study shows that the lesser π-extended system [9]HBNG shows the strongest electron donor character, in part by interlayer exchange resonance, and more red-shifted values of emission. Furthermore, [9]HBNG also shows exceptional chiroptical properties with the biggest values of gabs and glum (3.6 × 10-2) when compared to [10]HBNG and [11]HBNG owing to the fine alignment in the configuration of [9]HBNG between its electric and magnetic dipole transition moments. Furthermore, spectroelectrochemical studies as well as the fluorescence spectroscopy support the aforementioned experimental findings, thus confirming the strong impact of the helicene length on the properties of this new family of bilayer nanographenes.

How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain?

Tumour suppressor p53 plays a key role in the development of cancer and has therefore been widely studied in recent decades. While it is well known that p53 is biologically active as a tetramer, the tetramerisation mechanism is still not completely understood. p53 is mutated in nearly 50% of cancers, and mutations can alter the oligomeric state of the protein, having an impact on the biological function of the protein and on cell fate decisions. Here, we describe the effects of a number of representative cancer-related mutations on tetramerisation domain (TD) oligomerisation defining a peptide length that permits having a folded and structured domain, thus avoiding the effect of the flanking regions and the net charges at the N- and C-terminus. These peptides have been studied under different experimental conditions. We have applied a variety of techniques, including circular dichroism (CD), native mass spectrometry (MS) and high-field solution NMR. Native MS allows us to detect the native state of complexes maintaining the peptide complexes intact in the gas phase; the secondary and quaternary structures were analysed in solution by NMR, and the oligomeric forms were assigned by diffusion NMR experiments. A significant destabilising effect and a variable monomer population were observed for all the mutants studied.

Validation of circulating histone detection by mass spectrometry for early diagnosis, prognosis, and management of critically ill septic patients.

BACKGROUND: As leading contributors to worldwide morbidity and mortality, sepsis and septic shock are considered a major global health concern. Proactive biomarker identification in patients with sepsis suspicion at any time remains a daunting challenge for hospitals. Despite great progress in the understanding of clinical and molecular aspects of sepsis, its definition, diagnosis, and treatment remain challenging, highlighting a need for new biomarkers with potential to improve critically ill patient management. In this study we validate a quantitative mass spectrometry method to measure circulating histone levels in plasma samples for the diagnosis and prognosis of sepsis and septic shock patients. METHODS: We used the mass spectrometry technique of multiple reaction monitoring to quantify circulating histones H2B and H3 in plasma from a monocenter cohort of critically ill patients admitted to an Intensive Care Unit (ICU) and evaluated its performance for the diagnosis and prognosis of sepsis and septic shock (SS). RESULTS: Our results highlight the potential of our test for early diagnosis of sepsis and SS. H2B levels above 121.40 ng/mL (IQR 446.70) were indicative of SS. The value of blood circulating histones to identify a subset of SS patients in a more severe stage with associated organ failure was also tested, revealing circulating levels of histones H2B above 435.61 ng/ml (IQR 2407.10) and H3 above 300.61 ng/ml (IQR 912.77) in septic shock patients with organ failure requiring invasive organ support therapies. Importantly, we found levels of H2B and H3 above 400.44 ng/mL (IQR 1335.54) and 258.25 (IQR 470.44), respectively in those patients who debut with disseminated intravascular coagulation (DIC). Finally, a receiver operating characteristic curve (ROC curve) demonstrated the prognostic value of circulating histone H3 to predict fatal outcomes and found for histone H3 an area under the curve (AUC) of 0.720 (CI 0.546-0.895) p < 0.016 on a positive test cut-off point at 486.84 ng/mL, showing a sensitivity of 66.7% and specificity of 73.9%. CONCLUSIONS: Circulating histones analyzed by MS can be used to diagnose SS and identify patients at high risk of suffering DIC and fatal outcome.

Genetic footprints of a rapid and large-scale range expansion: the case of cyclic common vole in Spain.

In the Anthropocene, many species are rapidly shifting their ranges in response to human-driven habitat modifications. Studying patterns and genetic signatures of range shifts helps to understand how species cope with environmental disturbances and predict future shifts in the face of global environmental change. We investigated the genetic signature of a contemporary wide-range expansion observed in the Iberian common vole Microtus arvalis asturianus shortly after a colonization event. We used mtDNA and microsatellite data to investigate patterns of genetic diversity, structure, demography, and gene flow across 57 localities covering the historical range of the species and the newly colonized area. The results showed a genetic footprint more compatible with a true range expansion (i.e. the colonization of previously unoccupied areas), than with a model of "colonization from within" (i.e. local expansions from small, unnoticed populations). Genetic diversity measures indicated that the source population was likely located at the NE of the historical range, with a declining gradient of genetic diversity towards the more recently invaded areas. At the expansion front, we observed the greatest gene flow and smallest pairwise differences between nearby localities. Both natural landscape features (rivers) and recent anthropogenic barriers (roads, railways) explained a large proportion of genetic variance among populations and had a significant impact on the colonization pathways used by voles.

Pathogenesis in Pseudomonas aeruginosa PAO1 Biofilm-Associated Is Dependent on the Pyoverdine and Pyocyanin Siderophores by Quorum Sensing Modulation.

Pseudomonas aeruginosa is an opportunistic pathogenic bacterium for humans, animals, and plants, through producing different molecular factors such as biofilm, siderophores, and other virulence factors which favor bacterial establishment and infection in the host. In P. aeruginosa PAO1, the production of these factors is regulated by the bacterial quorum sensing (QS) mechanisms. From them, siderophores are involved in iron acquisition, transport, and homeostasis. They are also considered some of the main virulence factors in P. aeruginosa; however, detailed mechanisms to induce bacterial pathogenesis are poorly understood. In this work, through reverse genetics, we evaluated the function of bacterial pathogenesis in the pvd cluster genes, which are required for synthesizing the siderophore pyoverdine (PVD). Single pvdI, pvdJ, pvdL, and double mutant strains were analyzed, and contrary to expected, the pvdL and pvdI mutations increased the concentration of PVD and other phenazines, such as pyocyanin (PYO) and phenazine-1-carboxylic acid (PCA) and also an increased biofilm production and morphology depending on the autoinducer 2-alkyl-4-quinolone (PQS) and the QS molecules acyl-homoserine lactones. Consequently, in the in vivo pathogenicity model of Caenorhabditis elegans, the mutations in pvdI, pvdJ, and pvdL increased the survival of the worms exposed to supernatants or biofilms of the bacterial cultures. However, the double mutant pvdI/pvdJ increased its toxicity in agreeing with the biofilm production, PVD, PYO, and PCA. The findings indicate that the mutations in pvd genes encode non-ribosomal peptide synthetases impacted the biofilm's structure, but suppressively also of the phenazines, confirming that the siderophores contribute to the bacterial establishment and pathogenicity of P. aeruginosa PAO1.

Development of an α'-hydroxy enone for the aminocatalytic asymmetric formal conjugate addition of aldehydes to acrylates, vinyl ketones and acrolein.

Aminocatalytic asymmetric conjugate addition of aldehydes to Michael acceptors is a well established C-C bond forming methodology. However, various acrylic-type acceptors, including acrylic acid derivatives and acrolein, remain reluctant. Here we demonstrate that the internal H-bonding self-activation in α'-hydroxy enones allows them to react smoothly with enolizable aldehydes using commercially available aminocatalysts to afford adducts in good yields and high enantioselectivity. Straightforward conversion of the ketol moiety of these adducts into aldehyde, ketone and carboxylic acid functionalities offers an indirect, unified entry to products derived from acrolein, alkyl-vinyl ketones and acrylates, respectively.

Antitumor activity of bovine lactoferrin and its derived peptides against HepG2 liver cancer cells and Jurkat leukemia cells.

Liver cancer and leukemia are the fourth and first causes, respectively, of cancer death in children and adults worldwide. Moreover, cancer treatments, although beneficial, remain expensive, invasive, toxic, and affect the patient's quality of life. Therefore, new anticancer agents are needed to improve existing agents. Because bovine lactoferrin (bLF) and its derived peptides have antitumor properties, we investigated the anticancer effect of bLF and LF peptides (LFcin17-30, LFampin265-284 and LFchimera) on liver cancer HepG2 cells and leukemia Jurkat cells. HepG2 and Jurkat cells were incubated with bLF and LF peptides. Cell proliferation was quantified by an MTT assay, and cell morphology and damage were visualized by light microscopy or by phalloidin-TRITC/DAPI staining. The discrimination between apoptosis/necrosis was performed by staining with Annexin V-Alexa Fluor 488 and propidium iodide, and the expression of genes related to apoptosis was analyzed in Jurkat cells. Finally, the synergistic interaction of bLF and LF peptides with cisplatin or etoposide was assessed by an MTT assay and the combination index. The present study demonstrated that bLF and LF peptides inhibited the viability of HepG2 and Jurkat cells, inducing damage to the cell monolayer of HepG2 cells and morphological changes in both cell lines. bLF, LFcin17-30, and LFampin265-284 triggered apoptosis in both cell lines, whereas LFchimera induced necrosis. These results suggested that bLF and LF peptides activate apoptosis by increasing the expression of genes of the intrinsic pathway. Additionally, bLF and LF peptides synergistically interacted with cisplatin and etoposide. In conclusion, bLF and LF peptides display anticancer activity against liver cancer and leukemia cells, representing an alternative or improvement in cancer treatment.

Myocardial injury after major non-cardiac surgery evaluated with advanced cardiac imaging: a pilot study.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) is a frequent complication caused by cardiac and non-cardiac pathophysiological mechanisms, but often it is subclinical. MINS is associated with increased morbidity and mortality, justifying the need to its diagnose and the investigation of their causes for its potential prevention. METHODS: Prospective, observational, pilot study, aiming to detect MINS, its relationship with silent coronary artery disease and its effect on future adverse outcomes in patients undergoing major non-cardiac surgery and without postoperative signs or symptoms of myocardial ischemia. MINS was defined by a high-sensitive cardiac troponin T (hs-cTnT) concentration > 14 ng/L at 48-72 h after surgery and exceeding by 50% the preoperative value; controls were the operated patients without MINS. Within 1-month after discharge, cardiac computed tomography angiography (CCTA) and magnetic resonance imaging (MRI) studies were performed in MINS and control subjects. Significant coronary artery disease (CAD) was defined by a CAD-RADS category ≥ 3. The primary outcomes were prevalence of CAD among MINS and controls and incidence of major cardiovascular events (MACE) at 1-year after surgery. Secondary outcomes were the incidence of individual MACE components and mortality. RESULTS: We included 52 MINS and 12 controls. The small number of included patients could be attributed to the study design complexity and the dates of later follow-ups (amid COVID-19 waves). Significant CAD by CCTA was equally found in 20 MINS and controls (30% vs 33%, respectively). Ischemic patterns (n = 5) and ischemic segments (n = 2) depicted by cardiac MRI were only observed in patients with MINS. One-year MACE were also only observed in MINS patients (15.4%). CONCLUSION: This study with advanced imaging methods found a similar CAD frequency in MINS and control patients, but that cardiac ischemic findings by MRI and worse prognosis were only observed in MINS patients. Our results, obtained in a pilot study, suggest the need of further, extended studies that screened systematically MINS and evaluated its relationship with cardiac ischemia and poor outcomes. Trial registration Clinicaltrials.gov identifier: NCT03438448 (19/02/2018).

Mental fatigue changes from regular season to play-offs in semiprofessional soccer: A comparison by training days.

The main purpose was to compare by each training the mental load and fatigue reported by semiprofessional soccer players comparing between regular season phase and the play-offs. Fifty-three players (Mage  = 24.59 years) for two teams participated during the 2020/21 season. Mental load was measured with a Likert questionnaire. Mental fatigue was quantified with a Visual Analogue Scale. Four trainings were recorded each week (Monday = MD+1, Wednesday = MD-4, Thursday = MD-3 and Saturday = MD-1), with a competitive match on Sunday across 10 weeks (five dates of regular season - five dates of play-offs). A Linear Mixed Model was performed with R-studio, using the training days and the competitive phase as independent variables. The influence of time played as co-variable was also checked. Results showed MD+1 as the more mentally fatiguing day in both phases, although MD-4 were the training with higher mental load reported (p = 0.001). Comparing phases, mental fatigue was significantly higher during the play-offs (p = 0.037). With regard time played, players that did not usually play showed a decrease in mental load during the play-offs. Then, we recommend coaches to use recovery strategies for mental fatigue, avoid mentally fatiguing tasks close to competition and considerer the time played as a factor which may contribute to individual differences in player mental fatigue.

Do sport teams with greater team resilience perceive higher performance at the end of the season? A multilevel analysis.

A team's ability to respond positively to adversities, problems, and obstacles during their season is an essential part of success in collective sports. Grounded in team resilience theory and using a multilevel analytical approach, this study examined the relationship of the characteristics of resilience and vulnerability under pressure with perceived individual and team performance. Participants were 676 soccer players (530 males and 146 females) aged 15-42 years (M = 21.40, SD = 5.38), who played on 64 senior and under-18 soccer teams of several national leagues in Spain. In the final month of the season, factors related to team resilience and individual and team performance were analyzed. We estimated multilevel models by including perceived individual and team performance as dependent variables. Characteristics of resilience and vulnerability under pressure were considered as fixed and random effects (i.e., individual- and team-level intercepts and slopes). At the individual level, results showed that characteristics of resilience were positively associated with subjective individual and team performance, whereas vulnerability under pressure was negatively related to perceived team (but not individual) performance. At the team level, only characteristics of resilience positively predicted team performance. These findings suggest that more resilient teams report more successful performance from an individual and team perspective, whereas teams that are more vulnerable under pressure report poorer team performance. Taken together, the study underscores the importance of practitioners to develop strategies that improve their teams' resilience, given that team resilience helps to achieve positive subjective individual and team outcomes.

Comparison of the Rhizobacteria Serratia sp. H6 and Enterobacter sp. L7 on Arabidopsis thaliana Growth Promotion.

The genera Serratia and Enterobacter belong to the Enterobacteriaceae family and several members have been described as plant growth-promoting rhizobacteria (PGPR). However, how these bacteria influence growth and development is unclear. We performed in vitro interaction assays between either Serratia sp. H6 or Enterobacter sp. L7 with Arabidopsis thaliana seedlings to analyze their effects on plant growth. In experiments of co-cultivation distant from the root tip, Enterobacter sp. decreased root length, markedly increased lateral root number, and slightly increased plant biomass by 33%, 230%, and 69%, respectively, and relative to the control. The volatile organic compounds (VOCs) emitted from Serratia sp. H6 but not those from Enterobacter sp. L7 promoted Arabidopsis growth. A blend of volatile compounds from the two bacteria had effects on plant growth that were similar to those observed for volatile compounds from H6 only. At several densities, the direct contact of roots with Serratia sp. H6 had phytostimulant properties but Enterobacter sp. L7 had clear deleterious effects. Together, these results suggest that direct contact and VOCs of Serratia sp. H6 were the main mechanisms to promote plant growth of A. thaliana, while diffusible compounds of Enterobacter sp. L7 were predominant in their PGPR activity.

Identification of Marine Biotechnology Value Chains with High Potential in the Northern Mediterranean Region.

Marine (blue) biotechnology is an emerging field enabling the valorization of new products and processes with massive potential for innovation and economic growth. In the Mediterranean region, this innovation potential is not exploited as well as in other European regions due to a lack of a clear identification of the different value chains and the high fragmentation of business innovation initiatives. As a result, several opportunities to create an innovative society are being missed. To address this problem, eight Northern Mediterranean countries (Croatia, France, Greece, Italy, Montenegro, Portugal, Slovenia and Spain) established five national blue biotechnology hubs to identify and address the bottlenecks that prevent the development of marine biotechnology in the region. Following a three-step approach (1. Analysis: setting the scene; 2. Transfer: identification of promising value chains; 3. Capitalization: community creation), we identified the three value chains that are most promising for the Northern Mediterranean region: algae production for added-value compounds, integrated multi-trophic aquaculture (IMTA) and valorization aquaculture/fisheries/processing by-products, unavoidable/unwanted catches and discards. The potential for the development and the technical and non-technical skills that are necessary to advance in this exciting field were identified through several stakeholder events which provided valuable insight and feedback that should be addressed for marine biotechnology in the Northern Mediterranean region to reach its full potential.

Do Women Physicians Accept and Follow Heart Failure Guidelines More Than Men?

PURPOSE OF REVIEW: Our aim was to assess the degree of acceptance of the European Clinical Practice Guidelines (CPG) on heart failure (HF) among Spanish physicians according to sex. This was a cross-sectional study, employing Google Forms, conducted by a group of HF experts from the Region of Madrid (Spain), between November 2021 and February 2022, among specialists and residents of Cardiology, Internal Medicine, and Primary Care from Spain. RECENT FINDINGS: A total of 387 physicians-173 women (44.7%)-from 128 different centers completed the survey. Compared to men, women were significantly younger (38.2 ± 9.1 years vs. 40.6 ± 11.2 years; p = 0.024) and had fewer years of clinical practice (12.1 ± 8.1 years vs. 14.5 ± 10.7 years; p = 0.014). Briefly, women and men had a positive opinion of the guidelines and thought that implementing quadruple therapy is feasible in less than 8 weeks. Women followed more frequently than men the new paradigm of "4 pillars at lowest doses" and considered more frequently the establishment of quadruple therapy before implanting a cardiac device. Although they agreed about "low blood pressure" as the major limitation for achieving quadruple therapy in heart failure with reduced ejection fraction, there were discrepancies on the second most frequent barrier, and women were more proactive when initiating SGLT2 inhibitors. In a large survey including nearly 400 doctors from all over Spain to provide real-world opinion on 2021 ESC HF Guidelines and experience with SGLT2 inhibitors, women follow more frequently the new paradigm of "4 pillars at lowest doses", consider more frequently the establishment of quadruple therapy before implanting a cardiac device, and were more proactive when initiating SGLT2 inhibitors. Further studies confirming an association of sex with a better compliance of HF guidelines are needed.

Effect of Multi-walled Carbon Nanotubes Functionalized with Indol-3-butyric Acid on the Development of Avena sativa.

In pioneering research, it has been documented that the CNT influences the development of plants through the balance of phytoregulators. Therefore, in this work the objective is to evaluate the effects of CNT functionalized by non-covalent method with indole-3-butyric acid that they have on Avena sativa. The CNT was characterized by FTIR and Raman to confirm functionalization. It was observed that in the germination stage the seeds treated with IBA inhibited germination, however, when functionalizing the CNT with IBA it was observed that the CNT is contributing to counteract this inhibition.

Cost-effectiveness of a high-sensitivity cardiac troponin T systematic screening strategy compared with usual care to identify patients with peri-operative myocardial injury after major noncardiac surgery.

BACKGROUND: About 300 million surgeries are performed worldwide annually and this figure is increasing constantly. Peri-operative myocardial injury (PMI), detected by cardiac troponin (cTn) elevation, is a common cardiac complication of noncardiac surgery, strongly associated with short- and long-term mortality. Without systematic peri-operative cTn screening, most cases of PMI may go undetected. However, little is known about cost effectiveness of a systematic PMI screening strategy with high-sensitivity cardiac troponin T (hs-cTnT) after noncardiac surgery. OBJECTIVE: To assess, in patients with high cardiovascular risk, the cost-effectiveness of a systematic screening strategy using a hs-cTnT assay, to identify patients with PMI after major noncardiac surgery, compared with usual care. DESIGN: Cost-effectiveness analysis; single centre prospective cohort study. SETTING: Spanish University Hospital. PATIENTS: From July 2016 to March 2019, we included 1477 consecutive surgical patients aged ≥65 or if <65, with documented history of cardiovascular disease or impaired renal function, who underwent major noncardiac surgery and required at least an overnight hospital stay. We excluded patients aged <65 years without cardiovascular disease, undergoing minor surgery, or with an expected <24 h hospital stays. INTERVENTIONS: We conducted a decision-tree analysis, comparing a systematic screening strategy measuring hs-cTnT before surgery, and at the 2nd and 3rd days after surgery vs. a usual care strategy. We considered a third-party payer perspective and the outcomes of both strategies in the short-term (30 days follow-up). Information about costs was expressed in Euros-2021. We calculated the incremental cost-effectiveness ratio (ICER) of the systematic hs-cTnT strategy, defined as the expected cost per any additional PMI detected, and explored the robustness of the model using deterministic and probabilistic sensitivity analysis. MAIN OUTCOME MEASURES: ICER of the systematic hs-cTnT screening strategy. RESULTS: The ICER was €425 per any additionally detected PMI. The deterministic sensitivity analysis showed that a 15% variation in costs, and a 1% variation in the predictive values, had a minor impact over the ICER, except in case of the negative predictive value of the systematic hs-cTnT screening strategy. Monte Carlo simulations (probabilistic sensitivity analysis) showed that systematic hs-cTnT screening would be cost-effective in 100% of cases with a 'willingness to pay' of €780. CONCLUSIONS: Our results suggest that systematic peri-operative PMI screening with hs-cTnT may be cost-effective in the short-term in patients undergoing major noncardiac surgery. Economic evaluations, with a long-term horizon, are still needed. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03438448.

Transformers for Multi-Horizon Forecasting in an Industry 4.0 Use Case.

Recently, a novel approach in the field of Industry 4.0 factory operations was proposed for a new generation of automated guided vehicles (AGVs) that are connected to a virtualized programmable logic controller (PLC) via a 5G multi-access edge-computing (MEC) platform to enable remote control. However, this approach faces a critical challenge as the 5G network may encounter communication disruptions that can lead to AGV deviations and, with this, potential safety risks and workplace issues. To mitigate this problem, several works have proposed the use of fixed-horizon forecasting techniques based on deep-learning models that can anticipate AGV trajectory deviations and take corrective maneuvers accordingly. However, these methods have limited prediction flexibility for the AGV operator and are not robust against network instability. To address this limitation, this study proposes a novel approach based on multi-horizon forecasting techniques to predict the deviation of remotely controlled AGVs. As its primary contribution, the work presents two new versions of the state-of-the-art transformer architecture that are well-suited to the multi-horizon prediction problem. We conduct a comprehensive comparison between the proposed models and traditional deep-learning models, such as the long short-term memory (LSTM) neural network, to evaluate the performance and capabilities of the proposed models in relation to traditional deep-learning architectures. The results indicate that (i) the transformer-based models outperform LSTM in both multi-horizon and fixed-horizon scenarios, (ii) the prediction accuracy at a specific time-step of the best multi-horizon forecasting model is very close to that obtained by the best fixed-horizon forecasting model at the same step, (iii) models that use a time-sequence structure in their inputs tend to perform better in multi-horizon scenarios compared to their fixed horizon counterparts and other multi-horizon models that do not consider a time topology in their inputs, and (iv) our experiments showed that the proposed models can perform inference within the required time constraints for real-time decision making.