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Abstract Aims The HeartLogic algorithm combines multiple implantable defibrillator (ICD) sensor data and has proved to be a sensitive and timely predictor of impending heart failure (HF) decompensation in cardiac resynchronization therapy (CRT‐D) patients. We evaluated the performance of this algorithm in non‐CRT ICD patients and in the presence of co‐morbidities. Methods and results The HeartLogic feature was activated in 568 ICD patients (410 with CRT‐D) from 26 centres. The median follow‐up was 26 months [25th–75th percentile: 16–37]. During follow‐up, 97 hospitalizations were reported (53 cardiovascular) and 55 patients died. We recorded 1200 HeartLogic alerts in 370 patients. Overall, the time IN the alert state was 13% of the total observation period. The rate of cardiovascular hospitalizations or death was 0.48/patient‐year (95% CI: 0.37–0.60) with the HeartLogic IN the alert state and 0.04/patient‐year (95% CI: 0.03–0.05) OUT of the alert state, with an incidence rate ratio of 13.35 (95% CI: 8.83–20.51, P

Abstract Aims Specialist cardiology care is associated with a prognostic benefit in patients with heart failure (HF) with reduced ejection fraction (HFrEF) admitted with decompensated HF. However, up to one third of patients admitted with HF and normal ejection fraction (HFnEF) do not receive specialist cardiology input. Whether this has prognostic implications is unknown. Methods and results Data on patients hospitalized with HFnEF from two tertiary centres were analysed. The primary outcome measure was all‐cause mortality during follow‐up. The secondary outcome was in‐hospital mortality. A total of 1413 patients were included in the study. Of these, 23% (n = 322) did not receive in‐hospital specialist cardiology input. Patients seen by a cardiologist were less likely to have hypertension (73% vs. 79%, P = 0.03) and respiratory co‐morbidities (25% vs. 31%, P = 0.02) compared with those who did not receive specialist input. Similarly, clinical presentation was more severe for those who received specialist input (New York Heart Association III/IV 83% vs. 75% respectively, P = 0.003; moderate‐to‐severe peripheral oedema 65% vs. 54%, P

Abstract Drought is among the main abiotic factors causing agronomical losses worldwide. To minimize its impact, several strategies have been proposed, including the use of plant growth‐promoting bacteria (PGPBs), as they have demonstrated roles in counteracting abiotic stress. This aspect has been little explored in emergent crops such as quinoa, which has the potential to contribute to reducing food insecurity. Thus, here we hypothesize that the genotype, water environment and the type of inoculant are determining factors in shaping quinoa rhizosphere bacterial communities, affecting plant performance. To address this, two different quinoa cultivars (with contrasting water stress tolerance), two water conditions (optimal and limiting water conditions) and different soil infusions were used to define the relevance of these factors. Different bacterial families that vary among genotypes and water conditions were identified. Certain families were enriched under water stress conditions, such as the Nocardioidaceae, highly present in the water‐sensitive cultivar F15, or the Pseudomonadaceae, Burkholderiaceae and Sphingomonadaceae, more abundant in the tolerant cultivar F16, which also showed larger total polyphenol content. These changes demonstrate that the genotype and environment highly contribute to shaping the root‐inhabiting bacteria in quinoa, and they suggest that this plant species is a great source of PGPBs for utilization under water‐liming conditions.

Abstract Hypertrophic obstructive cardiomyopathy can be the phenotype of storage disorders as Fabry disease cardiomyopathy. In this instance, its recognition through GLA gene analysis and preventive administration of enzyme replacement therapy may reduce heart failure risk of surgical septal myectomy (SSM). A 59‐year‐old man was referred for SSM as dyspnoea and low threshold muscle fatigue associated to severe left ventricular outflow obstruction (gradient of 100 mmHg) due to both interventricular septal hypertrophy and mitral leaflet systolic anterior motion were not controlled by metoprolol 100 mg bid. Electrocardiogram showed sinus rhythm and a complete left bundle branch block. Cardiac magnetic resonance imaging showed a preserved left ventricular (LV) contractility (ejection fraction 70%) but failed to reveal reduced T1 mapping and fibrosis of postero‐lateral LV wall suggesting Fabry disease cardiomyopathy. Cardiac catheterization and coronary angiography documented increased LV end‐diastolic pressure but normal coronary arteries. SSM was followed by acute renal and heart failure with left ventricular ejection fraction declining to 35%. Histology of SSM showed regularly arranged severely enlarged cardiomyocytes containing extensive vacuoles that were intensely positive to immunofluorescence with anti‐Gb3 antibodies and appeared at electron microscopy to consist of myelin bodies suggesting the diagnosis of FD. This entity was confirmed by low blood levels of alpha‐galactosidase A (0.8 nmol/mL/h; NV > 1), high values of Lyso‐Gb3 (5.85 nmol/L; NV G in the exon 5 of GLA gene. This study emphasizes the importance of a genetic screening for FD before SSM be considered for hypertrophic obstructive cardiomyopathy.

Abstract The common cockle is a valuable bivalve species inhabiting the Atlantic European coasts. The parasite Marteilia cochillia has devastated cockle beds in the southern Galician (NW Spain) rias since 2012. Previous data suggested that cockles from Ría de Arousa acquired some resilience to this parasite through natural selection after consecutive annual marteiliosis outbreaks and candidate markers associated with marteiliosis resilience were identified using population genomics and transcriptomics approaches. Here, a common garden experiment was performed using a naïve stock (from Ría de Muros‐Noia) and an affected stock (from Ría de Arousa) to test this hypothesis. Breeders from both stocks were used to produce seed cohorts at hatchery, which were pre‐grown in a raft (outdoor nursery stage) and deployed in two shellfish beds affected by marteiliosis in Ría de Arousa (growing‐out stage). In both beds, the naïve stock showed high marteiliosis prevalence and was fully depleted in a short period, while the affected stock barely showed evidence of marteiliosis. A set of 45 SNPs putatively associated with marteiliosis resilience were fitted for MassARRAY genotyping to check their role in the differential resilience detected between both stocks. Though no significant differentiation was found between the naïve and the affected stocks with neutral markers, 28 SNPs showed significant divergence between them, suggesting that these SNPs were involved in directional selection during eight generations (to the most) of marteiliosis pressure (long‐term selection). Furthermore, signals of selection were also detected in the naïve stock along the marteiliosis outbreak in the growing‐out stage (short‐term selection) and six SNPs, all shared with the long‐term evaluation, showed consistent signals of differentiation according to the infection severity. Some of these SNPs were located within immune genes pertaining to families such as proteasome, ubiquitin, tumor necrosis factor, and glutathione S‐transferase. These resilience‐associated markers will be useful to recover cockle production in Galicia.

Reply to the discussion and comments of Azerêdo et al. (2023) and Schneider et al. (2023).

Abstract The reach of primary protection zones of transmission lines distance relays is affected when large power flows circulate through the transmission line prior to a short circuit occurrence. This can cause improper operation of the protection system in certain scenarios. In practice, protection zone adjustments are made by considering the apparent impedances obtained from short‐circuit simulations in the line of interest using standard methods such as IEC 60909‐0 or ANSI/IEEE C37.010. However, these short‐circuit calculation methods omit the existing operating conditions prior to the fault. Therefore, this work proposes a set of equations developed for calculating the apparent impedance seen by the distance relay in view of different types of short circuits, including the effects of power flow prior to the fault. These equations are then used to establish the distance primary protection zone settings. The analysis uses the mathematical expressions proposed of voltages and currents at the relay location, and the impedance diagrams obtained from simulated short circuits. Subsequently, the settings obtained with these equations are compared to those achieved using the IEC 60909‐0 standard, allowing for the differences in settings and their effectiveness. Finally, this procedure is applied to a part of the Ecuadorian Transmission System.

Abstract Objective Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a complex etiology that lacks biomarkers predicting disease progression. The objective of this study was to use longitudinal cerebrospinal fluid (CSF) samples to identify biomarkers that distinguish fast progression (FP) from slow progression (SP) and assess their temporal response. Methods We utilized mass spectrometry (MS)‐based proteomics to identify candidate biomarkers using longitudinal CSF from a discovery cohort of SP and FP ALS patients. Immunoassays were used to quantify and validate levels of the top biomarkers. A state‐transition mathematical model was created using the longitudinal MS data that also predicted FP versus SP. Results We identified a total of 1148 proteins in the CSF of all ALS patients. Pathway analysis determined enrichment of pathways related to complement and coagulation cascades in FPs and synaptogenesis and glucose metabolism in SPs. Longitudinal analysis revealed a panel of 59 candidate markers that could segregate FP and SP ALS. Based on multivariate analysis, we identified three biomarkers (F12, RBP4, and SERPINA4) as top candidates that segregate ALS based on rate of disease progression. These proteins were validated in the discovery and a separate validation cohort. Our state‐transition model determined that the overall variance of the proteome over time was predictive of the disease progression rate. Interpretation We identified pathways and protein biomarkers that distinguish rate of ALS disease progression. A mathematical model of the CSF proteome determined that the change in entropy of the proteome over time was predictive of FP versus SP.

Abstract To evaluate the diagnostic value of the combination of two broad‐range PCR assays targeting two different and conserved regions of the viral genome for the diagnosis of acute Hepatitis E virus (HEV) infection. Patients with acute hepatitis were prospectively recruited. In all, HEV‐IgM antibodies were tested together with evaluation of HEV viraemia by two PCR assays (ORF3 and ORF1). The number of individuals exhibiting negative IgM antibody results but carrying viral RNA was calculated by each PCR assay. Four‐hundred and seventy individuals were included, of whom 145 (30.8%) were diagnosed as having acute HEV. Of them, 122 (84.1%) exhibited HEV‐IgM antibodies, and 81 (55.8%) had detectable viral RNA for at least one PCR. Using the ORF3 molecular assay, 70 (48.3%) individuals were identified with HEV infection. When the ORF1 molecular assay was applied, 49 (33.8%) individuals were identified. The ORF3 assay detected viral RNA in 32 patients not detected by the ORF1 assay. In contrast, the ORF1 assay could amplify viral RNA in 11 patients who were not detected by the ORF3 assay. The parallel use of two broad‐range PCR assays significantly increased the performance of the molecular diagnosis of HEV.

Abstract The pan‐European power grid is experiencing an increasing penetration of Variable Renewable Energy (VRE). The fluctuating and non‐dispatchable nature of VRE hinders them in providing the Ancillary Service (AS) needed for the reliability and stability of the grid. Therefore, Energy Storage Systems (ESS) are needed along the VRE. Among the different ESS, a particularly viable and reliable option is Pumped Hydro Storage (PHS), given its cost‐effective implementation and considerable lifespan, in comparison to other technologies. Traditional PHS plants with Francis turbines operate at a high head difference. However, not all regions have the necessary topology to make these plants cost‐effective and efficient. Therefore, the ALPHEUS project will introduce low‐head PHS for regions with a relatively flat topography. In this paper, a grid‐forming controlled converter coupled with low‐head PHS that can contribute to the grid stability is introduced, emphasising its ability to provide different AS, especially frequency control, through the provision of fast Frequency Containment Reserve (fFCR) as well as synthetic system inertia. This paper is an extended version of the paper “The Contribution of Low‐head Pumped Hydro Storage to a successful Energy Transition”, which was presented at the 19th Wind Integration Workshop 2020.

Abstract Background The gradual ageing of the population, and its effect on public spending, constitutes an urgent challenge for advanced economies. Through this study, we analyse the effect of older people, and their health and individual characteristics, on public health spending. Methods Using logistic regression methods, we have analysed the use of different health services and health technologies by older people in Spain, controlled for several health, socioeconomic, and other individual factors. Results The main factors that explain the consumption of both health services and health technology, above age, are related to the so‐called need factors: self‐reported health status, presence of chronic diseases, and disability. Conclusion Knowing the main factors that imply greater public health spending is a topic of special interest for designing efficient health policies, in a context of growth in public health spending. In this way, preventive attention on the so‐called need factors may be an important driver to improve the effectiveness of spending.

Abstract Introduction The gut microbiota (GM) can influence the pathogenesis of immune‐mediated adverse events (irAEs). Proton pump inhibitors (PPIs) can affect the integrity of GM, but their role in promoting irAEs is still poorly understood. Methods In this retrospective single‐center cohort study, the primary endpoint was the evaluation of the incidence of gastrointestinal (GI) irAEs in cancer patients on PPIs (exposed) versus cancer patients who were not on PPIs (unexposed). Results Three hundred and sixty three patients' records (248 M/115F, median age 69) were reviewed. Twenty‐three exposed patients (92%) developed GI irAEs while only two unexposed patients (8%) developed GI irAEs (hazard ratio [HR] 13.22, 95% confidence interval [CI] 3.11–56.10, p

Abstract Objective Circadian and multidien cycles of seizure occurrence are increasingly discussed as to their biological underpinnings and in the context of seizure forecasting. This study analyzes if patient reported seizures provide valid data on such cyclical occurrence. Methods We retrospectively studied if circadian cycles derived from patient‐based reporting reflect the objective seizure documentation in 2003 patients undergoing in‐patient video‐EEG monitoring. Results Only 24.1% of more than 29000 seizures documented were accompanied by patient notifications. There was cyclical underreporting of seizures with a maximum during nighttime, leading to significant deviations in the circadian distribution of seizures. Significant cyclical deviations were found for focal epilepsies originating from both, frontal and temporal lobes, and for different seizure types (in particular, focal unaware and focal to bilateral tonic–clonic seizures). Interpretation Patient seizure diaries may reflect a cyclical reporting bias rather than the true circadian seizure distributions. Cyclical underreporting of seizures derived from patient‐based reports alone may lead to suboptimal treatment schemes, to an underestimation of seizure‐associated risks, and may pose problems for valid seizure forecasting. This finding strongly supports the use of objective measures to monitor cyclical distributions of seizures and for studies and treatment decisions based thereon.

Abstract Background The World Health Organization proposed the concept of intrinsic capacity (IC; the composite of all the physical and mental capacities of the individual) as central for healthy ageing. However, little research has investigated the interaction and joint associations of IC with cardiovascular disease (CVD) incidence and CVD mortality in middle‐ and older‐aged adults. Methods Using data from 443 130 UK Biobank participants, we analysed seven biomarkers capturing the level of functioning of five domains of IC to calculate a total IC score (ranging from 0 [better IC] to +4 points [poor IC]). Associations between IC score and incidence of six long‐term CVD conditions (hypertension, stroke/transient ischaemic attack stroke, peripheral vascular disease, atrial fibrillation/flutter, coronary artery disease and heart failure), and grouped mortality from these conditions were estimated using Cox proportional models, with a 1‐year landmark analysis to triangulate the findings. Results Over 10.6 years of follow‐up, CVD morbidity grouped (n = 384 380 participants for the final analytic sample) was associated with IC scores (0 to +4): mean hazard ratio (HR) [95% confidence interval, CI] 1.11 [1.08–1.14], 1.20 [1.16–1.24], 1.29 [1.23–1.36] and 1.56 [1.45–1.59] in men (C‐index = 0.68), and 1.17 [1.13–1.20], 1.30 [1.26–1.36], 1.52 [1.45–1.59] and 1.78 [1.67–1.89] in women (C‐index = 0.70). In regard to mortality, our results indicated that the higher IC score (+4 points) was associated with a significant increase in subsequent CVD mortality (mean HR [95% CI]: 2.10 [1.81–2.43] in men [C‐index = 0.75] and 2.29 [1.85–2.84] in women [C‐index = 0.78]). Results of all sensitivity analyses by full sample, sex and age categories were largely consistent independent of major confounding factors (P

Abstract Background Parameters of body composition have prognostic potential in patients with oncologic diseases. The aim of the present study was to analyse the prognostic potential of radiomics‐based parameters of the skeletal musculature and adipose tissues in patients with advanced hepatocellular carcinoma (HCC). Methods Radiomics features were extracted from a cohort of 297 HCC patients as post hoc sub‐study of the SORAMIC randomized controlled trial. Patients were treated with selective internal radiation therapy (SIRT) in combination with sorafenib or with sorafenib alone yielding two groups: (1) sorafenib monotherapy (n = 147) and (2) sorafenib and SIRT (n = 150). The main outcome was 1‐year survival. Segmentation of muscle tissue and adipose tissue was used to retrieve 881 features. Correlation analysis and feature cleansing yielded 292 features for each patient group and each tissue type. We combined 9 feature selection methods with 10 feature set compositions to build 90 feature sets. We used 11 classifiers to build 990 models. We subdivided the patient groups into a train and validation cohort and a test cohort, that is, one third of the patient groups. Results We used the train and validation set to identify the best feature selection and classification model and applied it to the test set for each patient group. Classification yields for patients who underwent sorafenib monotherapy an accuracy of 75.51% and area under the curve (AUC) of 0.7576 (95% confidence interval [CI]: 0.6376–0.8776). For patients who underwent treatment with SIRT and sorafenib, results are accuracy = 78.00% and AUC = 0.8032 (95% CI: 0.6930–0.9134). Conclusions Parameters of radiomics‐based analysis of the skeletal musculature and adipose tissue predict 1‐year survival in patients with advanced HCC. The prognostic value of radiomics‐based parameters was higher in patients who were treated with SIRT and sorafenib.

Abstract Aims Interleukin‐1 (IL‐1) blockade may improve exercise capacity in patients with heart failure (HF) patients. The extent of the improvement and its persistence beyond discontinuation of IL‐1 blockade is unknown. Methods and results The primary objective was to determine changes in cardiorespiratory fitness and cardiac function on‐treatment with IL‐1 blocker, anakinra, and off‐treatment, after treatment cessation. We performed cardiopulmonary exercise testing, Doppler echocardiography, and biomarkers in 73 patients with HF, 37 (51%) females, 52 (71%) Black–African–American, before and after treatment with anakinra 100 mg daily. In a subset of 46 patients, testing was also repeated after treatment cessation. Quality of life was assessed in each patient using standardized questionnaires. Data are presented as median and interquartile range. Treatment with anakinra for 4 [2–12] weeks was associated with a significant improvement in high‐sensitivity C‐reactive protein (from 6.2 [3.3–15.4] to 1.4 [0.8–3.4] mg/L, P

Abstract Aims The presence of anti‐human leucocyte antigen (HLA) antibodies has been implicated in a higher incidence of complications as well as mortality rate in heart transplantation. The aim of the study was to identify through non‐invasive parameters early signs of myocardial dysfunction in the presence of anti‐HLA antibodies but without evidence of antibody‐mediated rejection (AMR) and its possible prognostic impact. Methods and results A total of 113 heart‐transplanted patients without acute cellular rejection (ACR) and AMR or cardiac allograft vasculopathy (CAV) were prospectively enrolled and divided into two groups [‘HLA+’ (50 patients) and ‘HLA−’ (63 patients)], based on the presence of anti‐HLA antibodies. Each patient was followed for 2 years after the enrolment, recording episodes of AMR, ACR, CAV, and mortality. Clinical characteristics were similar between the two groups. Among laboratory data, N‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity cardiac troponin values were significantly higher in the presence of anti‐HLA antibodies (P

Abstract Baroreflex activation therapy (BAT) is a possible adjuvant treatment for patients with heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy and may be an alternative therapy in patients with contraindications or drug intolerance. Our aim was to evaluate the efficacy and safety of BAT in patients with HFrEF. The protocol for this study was registered with PROSPERO (CRD42022349175). Searches were conducted using MEDLINE, preMedLine (via PubMed), EMBASE, Cochrane Library, Web of Science, Trip Medical Database, WHO International Clinical Trials Registry, and ClinicalTrials.gov. We included randomized controlled trials that compared the effects of BAT with pharmacological treatment. We assessed the risk of bias of each study using the Cochrane RoB2 tool and the certainty of the results using the GRADE approach. We performed a meta‐analysis of treatment effects using a fixed‐effects or random‐effects model, depending on the heterogeneity observed. Two studies were included in the meta‐analysis (HOPE4HF and BeAT‐HF). The results showed that BAT led to statistically significant improvements in New York Heart Association functional class (relative risk 2.13; 95% confidence interval [CI, 1.65 to 2.76]), quality of life (difference in means −16.97; 95% CI [−21.87 to −12.07]), 6 min walk test (difference in means 56.54; 95% CI [55.67 to 57.41]) and N‐terminal probrain natriuretic peptide (difference in means −120.02; 95% CI [−193.58 to −46.45]). The system‐ and procedure‐related complication event‐free rate varied from 85.9% to 97%. The results show that BAT is safe and improves functional class, quality of life and congestion in selected patients with HFrEF. Further studies and long‐term follow‐up are needed to assess efficacy in reducing cardiovascular events and mortality.

Abstract With the increasing demand for wind energy, it is important to be able to understand and predict the available wind resources. To that end, the present wind tunnel study addresses the flow in the induction and entrance region of wind farms through particle image velocimetry, with focus on differences between actuator disks and two‐bladed rotating wind turbine models. Both staggered and aligned farm layouts are examined for three different incoming wind directions. For each layout, 69 disks or turbines are used, and the field of view ranges from 12 rotor diameters upstream of the farms to 8 diameters downstream of the first row. The results show that the induction, or blockage effect, is higher for the disks, even though the thrust (or drag) coefficient is the same. In contrast, the wake is stronger downstream of the turbines. The orientation and layout of the farm do not have a major impact on the results. Modal decomposition of the flow shows that the flow structure similarity between the disk and turbines improves downstream of the second row of wake generating objects, indicating that the substitution of wind turbines by actuator disks is more appropriate for wind farms than for the investigation of single wakes.

Abstract Aim To know the attitudes towards sexuality of nursing students and those sociodemographic and cultural factors that can influence it. Design An observational study was carried out on Nursing degree students. One hundred and eighteen nursing degree students who were going to take the sexual and reproductive health nursing course. Methods A self‐administered online questionnaire. This questionnaire had several parts specifically designed to collect sociodemographic variables. In order to determine the attitudes towards sexuality, the questionnaire based on the ATSS (Attitudes Towards Sexuality Scale). The Double Standard Scale (DSS) was also used. This scale evaluates double standards within the area of sexuality. The Rape Supportive Attitude Scale (RSAS), was included to determine beliefs about rape, rapists and their victims. Results The ATSS shows a statistically significant association with religious beliefs (p = 0.005), with mean scores of 113.84 (SD = 9.81) for non‐believers (no religion), 108.36 (SD = 15.68) for non‐practicing believers and 102.32 (SD = 17.87) for believers (those who practice their faith). The mean score in the DSS shows a statistically significant association with alcohol consumption (p = 0.001). The mean score on the RSAS is statistically significantly associated with the place of residence (p = 0.050), the means were 44.32 (SD = 9.26) for those who lived in the city, 34.94 (SD = 19.21) if the place of residence was between 10,000 and 5000 inhabitants and 32.54 (SD = 15.01) if the family home was in a town with less than 5000 inhabitants. Conclusion Religious beliefs reduce liberalism and positive attitudes towards sexuality, whereas sporadic alcohol consumption increases them. Patient or Public Contribution No patient or public contribution.

Abstract Purpose This study assessed sustainable return to work (SRTW) of breast cancer survivors (BCS). Methods We used data from the prospective French cohort, CANTO. We included 1811 stage I–III BCS who were 50 (OR = 0.59; 95%CI = 0.43–0.82), stage III (2.56; 1.70–3.85), tumour subtype HR+/HER2+ (0.61; 0.39–0.95), severe fatigue (1.45; 1.06–1.98), workplace accommodations (1.63; 1.14–2.33) and life priorities (0.71; 0.53–0.95). Unemployment was associated with age > 50 (0.45; 0.29–0.72), working in the public sector (0.31; 0.19–0.51), for a small company (3.00; 1.74–5.20) and having a fixed‐term contract (7.50; 4.74–11.86). Conclusions A high number of BCS have periods of sick leave or unemployment after RTW. The determinants differ between sick leave and unemployment. Implications for cancer survivors BCS need to be supported even after RTW, which should be regarded as a process.

Abstract Objective To analyze the relationship between tumor volume in Endometrial Cancer (EC) on Magnetic Resonance Imaging (MRI) and lymph node metastasis to establish which patients benefit from omitting the lymphadenectomy. Methods A retrospective observational study with 194 patients with EC identified between 2016 and 2021 at the Juan Ramón Jiménez University Hospital, Huelva (Spain) was carried out. Preoperative MRI of 127 patients was assessed. The tumor volume was analyzed on MRI by the ellipsoid formula and another alternative method with a manual ROI in different sections. Risk factors for node metastases were analyzed to understand its relationship and to identify an optimum criterion for the tailored surgery. Results Univariate analysis showed risk factors for lymph node metastases were histological grade (p = 0.001), tumor with a volume greater than >25 cm3 (p 28 (p 25 cm3 was an independent risk factor for lymph node metastases. The patients without significant proposed risk factors (volume index >25 cm3 [OR = 0.64], Ca 125 > 28 [OR = 0.32], and high histological grade [OR = 2.6]) did not present lymph node metastases, independent of myometrial invasion. Conclusions Lymphadenectomy can be omitted in patients with Endometrioid carcinoma that do not have any of the following risk factors: high‐grade tumor, elevated Ca 125 (>28), and tumor volume on MRI greater than 25 cm3. Tumor volume might predict the state of lymph nodes in EC and it could give information regarding surgical management.

Abstract Background Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population‐based ALS cohort using readily available hematological indexes. Methods We collected clinical data and the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d'Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocytes populations, neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), systemic‐immune‐inflammation index (SII), and lymphocyte‐to‐monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex‐ and age‐based subgroups. Results Neutrophils (P = 0.001) and markers of increased innate immunity (NLR, P = 0.008 and SII, P = 0.006) were associated with a faster disease progression. Similarly, elevated innate immunity correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415). Conclusions and Relevance The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.

Abstract Although epilepsy surgery is the only curative therapeutic approach for lesional drug‐resistant epilepsy (DRE), there is reluctance to operate on infants due to a fear of complications. A recent meta‐analysis showed that epilepsy surgery in the first 6 months of life can achieve seizure control in about two thirds of children. However, robust data on surgical complications and postoperative cognitive development are lacking. We performed a retrospective multicenter study of infants who underwent epilepsy surgery in the first 6 months of life. 15 infants underwent epilepsy surgery at a median age of 134 days (IQR: 58) at four centers. The most common cause was malformation of cortical development, and 13 patients underwent a hemispherotomy. Two thirds required intraoperative red blood transfusions. Severe intraoperative complications occurred in two patients including death in one infant due to cardiovascular insufficiency. At a median follow‐up of 1.5 years (IQR: 1.8), 57% of patients were seizure‐free. Three patients where reoperated at a later age, resulting in 79% seizure freedom. Anti‐seizure medication could be reduced in two thirds, and all patients improved in their development. Our findings suggest that early epilepsy surgery can result in good seizure control and developmental improvement. However, given the perioperative risks, it should be performed only in specialized centers.

Abstract Background The Janus kinase (JAK)1/JAK2 inhibitor baricitinib in combination with topical corticosteroids (TCS) improved moderate‐to‐severe atopic dermatitis (AD) in the phase 3 BREEZE‐AD7 trial. Patients with previous systemic therapy may have more severe, treatment‐resistant disease. Objectives To assess the efficacy of baricitinib 4 mg in adults with moderate‐to‐severe AD with and without previous use of systemic therapy. Methods Patients were randomized 1:1:1 to TCS plus once‐daily oral placebo, 2 mg baricitinib or 4 mg baricitinib for 16 weeks. Outcomes were assessed in patients treated with baricitinib 4 mg with and without previous use of systemic therapy (N = 68, N = 43) versus placebo (N = 75, N = 34). Prior use of systemic therapy was defined as treatment of AD with oral corticosteroids, immunosuppressants or biologics. Endpoints included the proportions of patients achieving a vIGA‐AD® score 0 or 1 with >2‐point improvement from baseline, 75% improvement in the Eczema area and severity index score (EASI75), ≥4‐point improvement on the Itch numeric rating scale (NRS) and ≥4‐point improvement in the dermatology life quality index (DLQI). Logistic regression was used to evaluate consistent treatment effects across subgroups. Results At Week 16, among patients with and without previous use of systemics treated with baricitinib 4 mg versus placebo, respectively, vIGA‐AD score (0, 1) was achieved in 27.9% and 34.9% versus 13.3% and 17.6%, EASI75 was met in 47.1% and 48.8% versus 22.7% and 23.5%, Itch NRS ≥ 4‐point improvement was observed in 44.4% and 43.2% versus 14.1% and 33.3% and DLQI ≥ 4‐point improvement was seen in 75.8% and 69.2% versus 52.1% and 54.8%. Consistent treatment effects were observed between patients with or without prior use of systemics (treatment‐by‐subgroup interactions p = 0.085 for Itch NRS, p > 0.1 for all others). Conclusions Baricitinib 4 mg significantly reduced disease severity in AD compared to placebo regardless of prior systemic therapy.

Abstract Background The oral anti‐janus kinase 1 inhibitor upadacitinib has shown a good efficacy–safety profile in the treatment of moderate‐to‐severe atopic dermatitis (AD) in clinical trials; however, few data from real clinical practice have been published so far. Objectives To evaluate the efficacy and safety of upadactinib in clinical practice. Methods An observational and multicentric study was conducted. Inclusion criteria consisted of patients who had previously received upadacitinib in the clinical trial M19‐850 and continued treatment with upadacitinib (15 mg or 30 mg) under daily clinical practice conditions for 12 months. Demographic data, characteristics of AD, treatment response and adverse events were recorded. Preliminary results at 24‐week follow‐up are herein presented. Results A total of 26 patients (61.54% males, mean age: 35.58 years) were included in the study; of these, 92.31% received upadacitinib 30 mg at baseline. At 24 weeks, mean values of Eczema Area and Severity Index and body surface area were 2.26 and 2.37%, respectively, 82.35% of the patients reached the Investigator's Global Assessment 0/1 and the mean value of peak pruritus numerical rating scale was 1.74. Adverse events were present in 19.23% of the cases, causing one definitive treatment interruption (due to herpes zoster) and two temporary treatment discontinuations (due to temporary elevation of creatine kinase). Conclusions These data support the maintenance of the efficacy of upadacitinib at 24‐week posttrial follow‐up, with no unexpected safety concerns. More real‐world data are needed to confirm these results.

Abstract Aim To recognize, appraise and summarize the research evidence that has explored the results of pelvic floor muscle training on female sexual function. Design Systematic review and possible meta‐analysis. Methodology Between September and October 2022, the Cochrane Library, CINAHL, MEDLINE, EMBASE, PsycINFO and Scopus electronic databases will be searched. We will include RCT's in English, Spanish and Portuguese that investigate the results of pelvic floor muscle training on female sexual function. The data will be extracted by two researchers independently. Risk of bias will be measured from the Cochrane Risk of Bias Tool. The meta‐analysis of the results will be performed using Comprehensive Meta‐Analysis Version 2. Results This systematic review and possible meta‐analysis will contribute significantly to the promotion of pelvic floor health and women's sexual function and to strengthen clinical practice and define other areas of study.

Abstract Physical structures generated from ecosystem engineers can have a cascade of impacts on the ecological community and the surrounding landscape. The Eastern oyster Crassostrea virginica can form extensive intertidal reefs, whose three‐dimensional structures provide ecosystem services like nursery and foraging habitat for fishes and invertebrates and shoreline stabilization. Measurements of the structural properties of these reefs provide opportunities to quantitatively assess associated services. There is a growing variety of tools available for measuring three‐dimensional (3D) properties of intertidal habitats, including two remote sensing methods that capture 3D structural metrics in a number of environments. We surveyed reefs using a terrestrial laser scanner (TLS, LiDAR) and imagery from unoccupied aircraft systems (UAS, or drones) processed through Structure from Motion photogrammetry. Comparisons of digital elevation models from repetitive flights over an oyster reef to checkpoints yielded mean horizontal and vertical root mean square errors (RMSE) of −0.54 ± 0.47 cm and 0.97 ± 1.0 cm (Mean ± SD), respectively, indicating high accuracy among UAS surveys. Compared to TLS products, point cloud densities from UAS‐derived products were more consistent across the reef elevation gradient and much denser overall except in the low reef zone, which was proximal to most of the TLS scan locations. Comparisons of structural metrics between UAS and TLS showed similarities in metrics like profile and planform curvatures, yet indicated UAS surveys produced higher values of surface complexity and slope. Results indicate that UAS photogrammetry can produce robust oyster reef structural metrics that can be highly useful in oyster conservation and restoration.

Abstract Assessment of minimal residual disease in acute lymphoblastic leukemia by immune repertoire NGS requires spiking CDR3 sequences at known quantities into the patient's sample. Recently, the EuroClonality‐NGS group released one of the most comprehensive protocols for this purpose. ARResT/Interrogate is a closed‐source software for processing these NGS libraries, developed by this same group. Vidjil, an open‐source alternative, currently cannot handle libraries prepared using this protocol. Here, we present a Vidjil add‐on to solve this issue. EuroClonality‐NGS prepared samples analyzed with Vidjil and ARResT/Interrogate were highly concordant (r = 0.998) and presented low error (root‐mean‐square error, RMSE = 0.112).

Abstract The α4β1 integrin regulates the trafficking of multiple myeloma (MM) cells and contributes to MM disease progression. MicroRNAs (miRNAs) can have both tumor suppressor and oncogenic roles and thus are key controllers of tumor evolution, and have been associated with different phases of MM pathogenesis. Using small RNAseq analysis, we show here that α4β1‐dependent MM cell adhesion regulates the expression of forty different miRNAs, therefore expanding our current view of the α4β1 involvement in MM cell biology. Specific upregulation of miR‐324‐5p and miR‐331‐3p in cells attached to α4β1 ligands was confirmed upon silencing the α4 integrin subunit, and their increased levels found to be dependent on Erk1/2‐ and PI3K‐Akt‐, but not Src‐dependent signaling. Enhanced miR‐324‐5p expression upon α4β1‐mediated MM cell adhesion aimed the hedgehog (Hh) component SMO, revealing that the miR‐324‐5p‐SMO module represents a α4β1‐regulated pathway that could control Hh‐dependent cellular responses in myeloma. Our results open new therapy research avenues around the α4β1 contribution to MM progression that deserve to be investigated.

Abstract Purpose In COVID‐19 era, all forms of access of patients to the sleep units should be reduced as much as possible when implementing telemedicine. In the field of obstructive sleep apnea (OSA) therapy with positive airway pressure (PAP) devices, telemedicine includes the use of built‐in software (BIS) and storage of PAPs and remote‐controlled data (BISrc data) that are processed and transmitted daily to sleep units. We compared two methods of evaluating the final residual severity of OSA patients in home PAP titration: BISrc data versus nocturnal portable multichannel monitoring (PM) data in PAP (reference method) and to verify whether the efficacy PAP therapy guided by BISrc data was clinically adequate. Methods We conducted a real‐life prospective study in newly diagnosed patients with OSA. Patients used an auto‐adjusting positive airway pressure (AirSense 10 ResMed) with a pulse oximeter that allows daily transfer of BISrc data (apnea hypopnea index [AHI] and SaO2) and remote changes in ventilator setting. Once the PAP titration was completed, the pressure value or ranges were kept constant for 3 days and home PM was repeated. Results There were 41 patients with moderate to severe OSA who completed the study. When considering AHI only, the diagnostic accuracy of BISrc on the third day was equal to 97.5%; when considering AHI > 10/h, ODI > 10/h, and SaO2

Snail1 is a transcriptional factor required for cancer‐associated fibroblast (CAF) activation, and mainly detected in CAFs in human tumors. In the mouse mammary tumor virus‐polyoma middle tumor‐antigen (MMTV‐PyMT) model of murine mammary gland tumors, Snai1 gene deletion, besides increasing tumor‐free lifespan, altered macrophage differentiation, with fewer expressing low levels of MHC class II. Snail1 was not expressed in macrophages, and in vitro polarization with interleukin‐4 (IL4) or interferon‐γ (IFNγ) was not altered by Snai1 gene depletion. We verified that CAF activation modified polarization of naïve bone‐marrow‐derived macrophages (BMDMΦs). When BMDMΦs were incubated with Snail1‐expressing (active) CAFs or with conditioned medium derived from these cells, they exhibited a lower cytotoxic capability than when incubated with Snail1‐deleted (inactive) CAFs. Gene expression analysis of BMDMΦs polarized by conditioned medium from wild‐type or Snai1‐deleted CAFs revealed that active CAFs differentially stimulated a complex combination of genes comprising genes that are normally induced by IL4, downregulated by IFNγ, or not altered during the two canonical differentiations. Levels of RNAs relating to this CAF‐induced alternative polarization were sensitive to inhibitors of factors specifically released by active CAFs, such as prostaglandin E2 and TGFβ. Finally, CAF‐polarized macrophages promoted the activation of the immunosuppressive regulatory T cells (T‐regs). Our results imply that an active CAF‐rich tumor microenvironment induces the polarization of macrophages to an immunosuppressive phenotype, preventing the macrophage cytotoxic activity on tumor cells and enhancing the activation of T‐reg cells.

Abstract Aims To evaluate the effectiveness of the ‘reserved therapeutic space’ intervention for improving the nurse–patient therapeutic relationship in acute mental health units in Spain. Design Multicentre intervention study with control group. Methods The study will be carried out in 12 mental health units. The ‘reserved therapeutic space’ intervention to be tested has been co‐designed and validated by both nurses and patients. The quality of the therapeutic relationship, the care received and perceived coercion among patients will be assessed. An estimated 131 patients per group are expected to participate. Funding was granted by the Instituto de Salud Carlos III. Co‐financed by the European Union (European Regional Development Fund (ERDF) (PI21/00605)) and College of Nurses of Barcelona (PR‐487/2021). The proposal was approved by all the Research Ethics Committees of participating centres. Results This project will lead to changes in clinical practice, transforming the current models of organization and care management in mental health hospitalization units. No patient or public contribution.

Abstract Aims Testosterone deficiency (TD) is associated with increased morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). However, data in women are scanty. The aim of this study was to investigate the prognostic impact of TD on women with HFrEF. Methods Among 480 patients prospectively enrolled in the T.O.S.CA. (Terapia Ormonale Scompenso CArdiaco) registry, a prospective, multicentre, nationwide, observational study, 94 women were included in the current analysis. The TD was defined as serum testosterone levels lower than 25 ng/dl. Data regarding clinical status, echocardiography, exercise performance, cardiovascular hospitalization, and survival after an average follow‐up of 36 months were analysed. Results Thirty patients (31.9%) displayed TD. TD was associated with lower tricuspid annular plane excursion (TAPSE) to pulmonary arterial systolic pressure PASP ratio (TAPSE/PASP) (P = 0.008), peak oxygen consumption (VO2 peak) (P = 0.03) and estimated glomerular filtration rate (P

Abstract Background Although thoracic auscultation (AUSC) in calves is quick and easy to perform, the definition of lung sounds is highly variable and leads to poor to moderate accuracy in diagnosing bronchopneumonia (BP). Hypothesis/Objectives Evaluate the diagnostic accuracy of an AUSC scoring system based on a standard lung sound nomenclature at different cut‐off values, accounting for the absence of a gold standard test for BP diagnosis. Animals Three hundred thirty‐one calves. Methods We considered the following pathological lung sounds: increased breath sounds (score 1), wheezes and crackles (score 2), increased bronchial sounds (score 3), and pleural friction rubs (score 4). Thoracic auscultation was categorized as AUSC1 (positive calves for scores ≥1), AUSC2 (positive calves for scores ≥2), and AUSC3 (positive calves for scores ≥3). The accuracy of AUSC categorizations was determined using 3 imperfect diagnostic tests with a Bayesian latent class model and sensitivity analysis (informative vs weakly informative vs noninformative priors and with vs without covariance between ultrasound and clinical scoring). Results Based on the priors used, the sensitivity (95% Bayesian confidence interval [BCI]) of AUSC1 ranged from 0.89 (0.80‐0.97) to 0.95 (0.86‐0.99), with a specificity (95% BCI) of 0.54 (0.45‐0.71) to 0.60 (0.47‐0.94). Removing increased breath sounds from the categorizations resulted in increased specificity (ranging between 0.97 [0.93‐0.99] and 0.98 [0.94‐0.99] for AUSC3) at the cost of decreased sensitivity (0.66 [0.54‐0.78] to 0.81 [0.65‐0.97]). Conclusions and Clinical Importance A standardized definition of lung sounds improved AUSC accuracy for BP diagnosis in calves.

In colorectal cancer, the mechanisms underlying tumor aggressiveness require further elucidation. Taking advantage of a large panel of human metastatic colorectal cancer xenografts and matched stem‐like cell cultures (m‐colospheres), here we show that the overexpression of microRNA 483‐3p (miRNA‐483‐3p; also known as MIR‐483‐3p), encoded by a frequently amplified gene locus, confers an aggressive phenotype. In m‐colospheres, endogenous or ectopic miRNA‐483‐3p overexpression increased proliferative response, invasiveness, stem cell frequency, and resistance to differentiation. Transcriptomic analyses and functional validation found that miRNA‐483‐3p directly targets NDRG1, known as a metastasis suppressor involved in EGFR family downregulation. Mechanistically, miRNA‐483‐3p overexpression induced the signaling pathway triggered by ERBB3, including AKT and GSK3β, and led to the activation of transcription factors regulating epithelial–mesenchymal transition (EMT). Consistently, treatment with selective anti‐ERBB3 antibodies counteracted the invasive growth of miRNA‐483‐3p‐overexpressing m‐colospheres. In human colorectal tumors, miRNA‐483‐3p expression inversely correlated with NDRG1 and directly correlated with EMT transcription factor expression and poor prognosis. These results unveil a previously unrecognized link between miRNA‐483‐3p, NDRG1, and ERBB3‐AKT signaling that can directly support colorectal cancer invasion and is amenable to therapeutic targeting.

Abstract Background Intrathoracic neurogenic tumors (INTs) are derived from nerve tissue and grow within the chest. Preoperative diagnosis can be challenging and only complete surgical exeresis enables confirmation of the suspected diagnosis. Here, we analyzed our experience on management of paravertebral lesions with solid and cystic patterns. Methods A monocentric retrospective study was conducted, which included 25 consecutive cases of ITNs in the period from 2010 to 2022. These cases had been surgically treated by thoracoscopic resection alone, or in combination with neurosurgery in the case of dumbbell tumors. The demographic and operative data along with complications were recorded and analyzed. Results Twenty‐five patients were diagnosed with a paravertebral lesion of which 19 (76%) had solid features and six (24%) had cystic features. The most common diagnosis was schwannoma (72%), followed by neurofibroma (20%) and malignant schwannoma (8%). In four cases (12%) the tumor showed an intraspinal extension. None of the patients had recurrence until 6 months of follow‐up. Comparison between the VATS and thoracotomy procedures showed that outcome of discharge on the postoperative day, on average, was 2.61 ± 0.5 versus 3.51 ± 0.53, respectively (p‐value

Abstract Background Poly (ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are approved for the treatment of various solid tumors. In gastric cancer, genes commonly harbor mutations in the homologous recombination DNA repair pathway, potentially increasing sensitivity to PARPi. Pamiparib (BGB‐290) is a small molecule inhibitor of PARP1 and PARP2. Methods The PARALLEL‐303 study (NCT03427814) investigated the efficacy and safety of pamiparib 60 mg orally (PO) twice daily (BID) versus placebo PO BID as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer that responded to platinum‐based first‐line chemotherapy. The primary endpoint of this double‐blind, randomized, global phase 2 study was progression‐free survival (PFS) (RECIST version 1.1; per investigator assessment). Secondary endpoints included overall survival (OS) and safety. Results In total, 136 patients were randomized 1:1 to receive pamiparib (n = 71) or placebo (n = 65). Median PFS was numerically longer with pamiparib versus placebo but did not reach statistical significance (3.7 months [95% confidence interval (CI): 1.9, 5.3] vs. 2.1 months [95% CI: 1.9, 3.8]; hazard ratio 0.8 [95% CI: 0.5, 1.2]; p = 0.1428). Median OS was 10.2 months (95% CI: 8.7, 16.3) in the pamiparib arm versus 12.0 months (95% CI: 8.2, not estimable) in the placebo arm. Overall, 8 patients (11.3%) in the pamiparib arm and 2 patients (3.1%) in the placebo arm experienced ≥1 TEAE leading to treatment discontinuation. Conclusions Maintenance pamiparib did not meet statistical significance for superiority versus placebo for PFS, but was well tolerated with few treatment discontinuations; no unexpected safety signals were identified.

Abstract Background Persistent air leak (PAL) is a common complication after video‐assisted thoracoscopic surgery (VATS) lobectomy. We aimed to evaluate whether the intraoperative quantitative measurement of air leaks using a mechanical ventilation test could predict PAL and identify those patients needing additional treatment for the prevention of PAL. Methods This was an observational, retrospective, single‐center study that included 82 patients who underwent VATS lobectomy with a mechanical ventilation test for VL. Only 2% of patients who underwent lobectomy surgery had persistent air leaks. Results At the end of lobectomy performed in patients with non‐small cell lung cancer, the lung was reinflated at a 25–30 mmH2O pressure and ventilatory leaks (VL) were calculated and in relation to the entity of the air leaks, we evaluated the most suitable intraoperative treatment to prevent persistent air leaks. Conclusion VL is an independent predictor of PAL after VATS lobectomy; it provides a real‐time intraoperative guidance to identify those patients who can benefit from additional intraoperative preventive interventions to reduce PAL.

Abstract Background Patients with advanced hepatocellular carcinoma (HCC) and poor liver function lack effective systemic therapies. Low‐energy electromagnetic fields (EMFs) can influence cell biological processes via non‐thermal effects and may represent a new treatment option. Methods This single‐site feasibility trial enrolled patients with advanced HCC, Child‐Pugh A and B, Eastern Cooperative Oncology Group 0–2. Patients underwent 90‐min amplitude‐modulated EMF exposure procedures every 2–4 weeks, using the AutEMdev (Autem Therapeutics). Patients could also receive standard care. The primary endpoints were safety and the identification of hemodynamic variability patterns. Exploratory endpoints included health‐related quality of life (HRQoL), overall survival (OS). and objective response rate (ORR) using RECIST v1.1. Results Sixty‐six patients with advanced HCC received 539 AutEMdev procedures (median follow‐up, 30 months). No serious adverse events occurred during procedures. Self‐limiting grade 1 somnolence occurred in 78.7% of patients. Hemodynamic variability during EMF exposure was associated with specific amplitude‐modulation frequencies. HRQoL was maintained or improved among patients remaining on treatment. Median OS was 11.3 months (95% confidence interval [CI]: 6.0, 16.6) overall (16.0 months [95% CI: 4.4, 27.6] and 12.0 months [6.4, 17.6] for combination therapy and monotherapy, respectively). ORR was 24.3% (32% and 17% for combination therapy and monotherapy, respectively). Conclusion AutEMdev EMF exposure has an excellent safety profile in patients with advanced HCC. Hemodynamic alterations at personalized frequencies may represent a surrogate of anti‐tumor efficacy. NCT01686412.

Abstract Software organisations aim to develop and maintain high‐quality software systems. Due to large amounts of behaviour data available, software organisations can conduct data‐driven software maintenance. Indeed, software quality assurance and improvement programs have attracted many researchers' attention. Bayesian Networks (BNs) are proposed as a log analysis technique to discover poor performance indicators in a system and to explore usage patterns that usually require temporal analysis. For this, an action research study is designed and conducted to improve the software quality and the user experience of a web application using BNs as a technique to analyse software logs. To this aim, three models with BNs are created. As a result, multiple enhancement points have been identified within the application ranging from performance issues and errors to recurring user usage patterns. These enhancement points enable the creation of cards in the Scrum process of the web application, contributing to its data‐driven software maintenance. Finally, the authors consider that BNs within quality‐aware and data‐driven software maintenance have great potential as a software log analysis technique and encourage the community to deepen its possible applications. For this, the applied methodology and a replication package are shared.

Liver cancer is the fourth most common cause of cancer‐related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co‐inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well‐tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.

Abstract The rheological properties of proteins play a role important in the fluid flow, pump selection, equipment design, and product development. In addition, it has been observed that the texture and mouthfeel of foods depend on the viscoelastic properties of their ingredients, especially those that show both elastic and viscous behavior, such as proteins. To improve the functional properties, including the rheological ones, proteins have been subjected to some physical treatments, such as ultrasound, which is considered an emerging green technology. Changes in the properties of proteins by high‐intensity ultrasound vary according to the equipment used, power, frequency, and time of sonication, as well as the intrinsic characteristics of the studied proteins. As pretreatment, ultrasound affects the rheological properties of proteins such as viscosity and storage and loss moduli due to the structural modification of its polypeptide chain, as a consequence of the cavitation phenomenon. In this review, we present the main results of the effect of high‐intensity ultrasound on the rheological properties of animal and vegetable proteins subjected to different conditions such as ultrasound device, power, frequency, wave amplitude, and exposure time mainly. In this context, the information from studies of the impact of ultrasound on the rheological properties of proteins from animal and vegetable sources is important to diversify its possible use as a food ingredient.

Abstract Background Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross‐sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle‐aged and older men. Methods This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40–79 years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey–Osterrieth Complex Figure (ROCF‐Copy and ROCF‐Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia‐defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow‐up of 4.3 years. Cross‐sectional associations between cognition, sarcopenia‐defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia‐defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders. Results In the whole cohort (n = 3233), ROCF‐Copy (β = 0.016; P