Search

The often well-developed microvasculature in pancreatic neuroendocrine tumors (PanNETs) has been studied from different perspectives. However, some detailed structural findings have received less attention. Our objective is to study an overlooked event in PanNETs: "enclosed vascular tufts" (EVTs). For this purpose, 39 cases of PanNETs were examined with conventional (including serial sections) and immunochemistry procedures. In typical EVTs, the results show: 1) an insulated terminal vascular area, with a globular (glomeruloid) aspect, formed by a cluster of coiled microvessels, presenting CD31-, CD34-positive endothelial cells, αSMA-positive pericytes, and perivascular CD34-positive stromal cells/telocytes, separated by a pseudoglandular space from the surrounding trabeculae of tumor neuroendocrine cells; and 2) a pedicle joining the insulated terminal vascular area, with connective tissue tracts around the enclosing tumor trabeculae. EVTs predominate in the trabecular and nested gyriform pattern of PanNETs, with tumor trabeculae that follow a ribbon coil (winding ribbon pattern) around small vessels, which acquire a tufted image. In EVTs, secondary modifications may occur (fibrosis, hyalinization, myxoid changes, and calcification), coinciding or not with those of the connective tracts. In conclusion, the typical characteristics of unnoticed EVTs allow them to be considered as a morphological sign of PanNETs (a vascular tuft sign). Further in-depth studies are required, mainly to assess the molecular pathways that participate in vascular tuft formation and its pathophysiological implications., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Background: In 2020, the coronavirus disease 2019 (COVID-19) pandemic caused disruptions in kidney replacement therapy (KRT) services worldwide. The aim of this study was to assess the effect of the COVID-19 pandemic in 2020 on the incidence of KRT, kidney transplantation activity, mortality and prevalence of KRT across Europe., Methods: Patients receiving KRT were included from 17 countries providing data to the European Renal Association Registry. The epidemiology of KRT in 2020 was compared with average data from the period 2017-2019. Changes occurring during the first and second waves of the pandemic were also explored., Results: The incidence of KRT was 6.2% lower in 2020 compared with 2017-2019, with the lowest point (-22.7%) during the first wave in April. The decrease varied across countries, was smaller in males (-5.2%) than in females (-8.2%) and was moderate for peritoneal dialysis (-3.7%) and haemodialysis (-5.4%) but substantial for pre-emptive kidney transplantation (-23.6%). The kidney transplantation rate decreased by 22.5%, reaching a nadir of -80.1% during the first wave, and was greatest for living donor kidney transplants (-30.5%). While in most countries the kidney transplantation rate decreased, in the Nordic/Baltic countries and Greece there was no clear decrease. In dialysis patients, mortality increased by 11.4% and was highest in those 65-74 years of age (16.1%), in those with diabetes as the primary renal disease (15.1%) and in those on haemodialysis (12.4%). In transplant recipients, the mortality was 25.8% higher, but there were no subgroups that stood out. In contrast to the rising prevalence of KRT observed over the past decades across Europe, the prevalence at the end of 2020 (N = 317 787) resembled that of 2019 (N = 317 077)., Conclusion: The COVID-19 pandemic has had a substantial impact on the incidence of KRT, kidney transplant activity, mortality of KRT and prevalence of KRT in Europe with variations across countries., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Gram-negative bacterial lipopolysaccharides (LPSs) trigger inflammatory reactions through Toll-like receptor 4 (TLR4) and prime myeloid cells for inflammasome activation. In phosphate-limited environments, bacteria reduce LPS and other phospholipid production and synthesize phosphorus-free alternatives such as amino-acid-containing lipids like the ornithine lipid (OL). This adaptive strategy conserves phosphate for other essential cellular processes and enhances bacterial survival in host environments. While OL is implicated in bacterial pathogenicity, the mechanism is unclear. Using primary murine macrophages and human mononuclear cells, we elucidate that OL activates TLR4 and induces potassium efflux-dependent nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3) activation. OL upregulates the expression of NLRP3 and pro-interleukin (IL)-1β and induces cytokine secretion in primed and unprimed cells. By contrast, in the presence of LPS, OL functions as a partial TLR4 antagonist and reduces LPS-induced cytokine secretion. We thus suggest that in phosphate-depleted environments, OL replaces LPS bacterial immunogenicity, while constitutively present OL may allow bacteria to escape immune surveillance., Competing Interests: Declaration of interests L.H.-N. and P.P. are co-founders of Viva In Vitro Diagnostics. P.P. is scientific advisor of Viva In Vitro diagnostics. K.S. is a co-inventor on patent applications for NLRP3 inhibitors licensed to Inflazome, Ltd., a company headquartered in Dublin, Ireland. Inflazome is developing drugs that target the NLRP3 inflammasome to address unmet clinical needs in inflammatory disease. K.S. served on the scientific advisory board of Inflazome in 2016–2017 and serves as a consultant to Quench Bio (USA) and Novartis (Switzerland)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chronic wounds are defined as those with disturbances in normal healing. They involve symptoms like exudate, odor, pain or impaired mobility, severely impacting life quality. In the case of patients with additional comorbidities, these are known to aggravate the healing impairment. Amniotic membrane (AM) is gaining attention for its regenerative potential, as it has shown promise in treating hard-to-heal wounds, such as diabetic foot ulcers. This work examines a series of five patients who, while suffering an array of other chronic conditions, were treated with AM for the management of non-healing chronic ulcers. Inclusion criteria involved patients with lesions that have been active at least for six weeks and resistant to multiple treatments, accompanied by complex underlying pathologies affecting cardiovascular, immune or renal functions. Exclusion criteria included untreated active infections and patients undergoing other experimental treatments. The mean age of the patients was 68.4 ± 5.2 years. Wounds were treated once a week with AM, following standardized procedures. The variables measured included pain levels, microorganism presence, wound reduction and the number of AM applications to recovery. The median pain VAS score decreased significantly from seven at the start to two at the end of procedures. Four out of five patients achieved complete epithelialization, while the remaining patient showed significant reductions of 40% in wound size after 14 months. Our results confirm how the application of AM is a safe and effective resource for the management of chronic wounds in patients with serious comorbidities, enhancing patients' quality of life, firstly by reducing pain, later by allowing recovery. Future research, including molecular analyses of wound exudates before and after AM treatment, can contribute to better understanding and fine tuning of this therapeutic resource.

Knee osteoarthritis (KOA) is a prevalent degenerative joint disease associated with pain, disability, and functional limitations. Kinesiophobia, the fear of movement, has been linked to disability and pain in KOA patients. This study aimed to analyze the relationship between kinesiophobia and symptoms of KOA. A comprehensive literature search was conducted in four electronic databases (PubMed/Medline, Web of Science, Scopus and Science Direct) with the following inclusion criteria: 1) recruited participants with diagnostic of knee osteoarthritis; 2) measures of pain, disability and/or functional limitation through questionnaires or physical tests; 3) articles exploring the correlation between kinesiophobia, and pain, disability, and/or functional limitation as principal or secondary outcome; 4) primary data studies (observational and experimental). A total of 17 studies involving 1,574 participants (mean age 61.04 ± 5.79 years) were included in the corresponding meta-analyses. Results showed a moderate correlation between kinesiophobia and disability (r = 0.519; p-value=0.004), and fair correlations of kinesiophobia with pain (r = 0.362; p-value<0.001), and functional limitation (r = 0.270; p-value<0.001). Despite high heterogeneity (I 2 : 89.4% for pain, 94.6% for disability, and 90.4% for functional limitation), 52% of studies displayed low risk of bias. In conclusion, kinesiophobia positively correlates with pain, disability, and functional limitation in KOA patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: There is little evidence on the impact of current recommendations on the use of antiplatelet therapy during the perioperative and periprocedural period in our setting. The aim of this study was to analyze the incidence and clinical impact of inappropriate use of antiplatelet therapy in a population of patients undergoing surgery or a diagnostic or therapeutic procedure in "real life" in Spain., Methods: A prospective multicenter observational study of patients treated with antiplatelet agents requiring intervention was conducted. The incidence of thrombotic and hemorrhagic events at 30 days was analyzed according to peri-intervention management of antiplatelet therapy., Results: We included 643 patients (31.9% women, 39.0% over 75 years of age), most of them (87.7%) receiving aspirin as antiplatelet therapy at a dose of 100mg/day. Indications for antiplatelet therapy were ischemic heart disease (44.9%), cerebrovascular disease (21.7%), and peripheral vascular disease (23.0%). Ischemic risk was low in 74.3%, while 51.6% had a low bleeding risk of the intervention. Periprocedural management was considered appropriate in 61.7% of cases. 30-day incidence of the combined primary endpoint of thrombotic events and major bleeding (12.1% versus 5.0%; p=0.002) and 30-day mortality (5.2% versus 1.5%; p=0.008) were significantly higher in patients with inappropriate periprocedural management of antiplatelet agents., Conclusions: Despite current recommendations for the use of antiplatelet drugs in the perioperative/periprocedural period, their implementation in the "real world" remains low. Inappropriate use is associated with an increased incidence of adverse events, both thrombotic and hemorrhagic., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Background: The adoption of robotic techniques in liver surgery introduces significant challenges for their safe integration within hepatobiliary surgery units. This study is designed to investigate the complexities associated with establishing a robotic surgery program., Methods: Data on robotic hepatobiliary surgeries were prospectively collected from October 2021 to October 2023. Historical cohorts from the institutional experiences for comparison were hand-assisted (HALS) and purely laparoscopic procedures (PLS). Inverse probability of treatment weighting and propensity score matching were employed to compare outcomes between PLS and robotic resections. The learning curve for robotic surgeries was evaluated by the cumulative sum method., Results: In this study, 454 patients were enrolled (113 robotic surgeries, 157 HALS, and 184 PLS). The posterosuperior segments resections were significantly higher in the robotic group (47.8%) compared to PLS (31.5%) and HALS (35.7%). There were no conversions in the robotic group, in PLS 2.7% and HALS 3.8%. The degree of difficulty according to the median of the IWATE score and IMM score was significantly higher in the robot group (p < 0.001 and p = 0.008, respectively). No significant differences in short-term outcomes were observed between robotic procedures and PLS in a matched subset of patients. Operative efficiency and blood loss improved significantly after the 75th robotic surgery patient, with high-difficulty cases (IWATE ≥ 10) incorporated from the beginning., Conclusion: This study suggests that robotic liver surgery in units with prior experience in minimally invasive liver surgery offers benefits, such as a lower conversion rate and a higher rate of successful difficult resections., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A diagnosis of type 1 diabetes in a young person can create vulnerability for sleep. Historically it has been rare for young people to be offered a closed-loop system soon after diagnosis meaning that studies examining sleep under these circumstances in comparison with standard treatment have not been possible. In this study, we examine sleep in young people (and their parents) who were provided with hybrid closed-loop therapy at diagnosis of type 1 diabetes versus those who receive standard treatment over a 2-year period., Methods: The sample comprised 97 participants (mean age = 12.0 years; SD = 1.7) from a multicenter, open-label, randomized, parallel trial, where young people were randomized to either hybrid closed-loop insulin delivery or standard care at diagnosis. Sleep was measured using actigraphy and the Pittsburgh Sleep Quality Index (PSQI) in the young people, and using the PSQI in parents., Results: Sleep in young people using hybrid closed-loop insulin delivery did not differ significantly compared with those receiving standard care (although there were nonsignificant trends for better sleep in the closed-loop group for 4 of the 5 sleep actigraphy measures and PSQI). Similarly, there were nonsignificant differences for sleep between the groups at 24 months (with mixed direction of effects)., Conclusions: This study assessed for the first time sleep in young people using a closed-loop system soon after diagnosis. Although sleep was not significantly different for young people using closed-loop insulin delivery as compared with those receiving standard care, the direction of effects of the nonsignificant results indicates a possible tendency for better sleep quality in the hybrid closed-loop insulin delivery group at the beginning of the treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EMS has received research support from Medical Research Council, Diabetes UK, National Institute for Health Research (NIHR), Abbott Diabetes Care and speaker honoraria: from Abbott Diabetes Care, Ypsomed, and Lilly Diabetes Care. CKB has received consulting fees from CamDiab and speaker honoraria from Ypsomed. JW has received speaker honoraria from Ypsomed and Novo Nordisk. MEW reports patents related to closed-loop and being a consultant at CamDiab. SH serves as a member of Medtronic advisory board, is a director of Ask Diabetes Ltd providing training and research support in health care settings, and reports having received training honoraria from Medtronic and Sanofi and consulting fees for CamDiab. TR receives consultancy fees from Abbott Diabetes care and has received honoraria from NovoNordisk for delivering educational meetings. REJB reports receiving speaker honoraria from Eli Lilly and Springer Healthcare, and reports sitting on the NovoNordisk UK Foundation Research Selection Committee on a voluntary basis. She acted as an independent advisor for Provent Bio, and received speaking honoraria from Sanofi and Medcape, which were donated to an education research fund. RH reports receiving speaker honoraria from Eli Lilly, Dexcom and Novo Nordisk, receiving license and/or consultancy fees from BBraun and Abbott Diabetes Care; patents related to closed-loop, and being director at CamDiab. AMG is an advisor for a project initially sponsored by Johnson’s Baby. She was a consultant for Perrigo (2021+). She receives royalties for two books Nodding Off (Bloomsbury Sigma, 2018) and The Sleepy Pebble (Flying Eye, 2019) and a sleep gift (The Gift of Sleep, Laurence King Publishers, 2023). She was previously a CEO of Sleep Universal LTD (2022). She is a regular contributor to BBC Focus Magazine and has contributed to other outlets (such as The Conversation, The Guardian, and Balance Magazine). She occasionally receives sample products related to sleep (eg, blue light–blocking glasses) and has given a paid talk to a business (Investec). She is a specialist subject editor at JCPP (sleep) for which she receives a small honorarium. She has contributed a paid article to Neurodiem.JJM-V, JMA, AT, AG, DE, NT, and FMC declare no competing financial interests.

Over the past 50 years, the number and invasiveness of percutaneous cardiovascular procedures globally have increased substantially. However, cardiovascular interventions are inherently associated with a risk of acute brain injury, both periprocedurally and postprocedurally, which impairs medical outcomes and increases health-care costs. Current international clinical guidelines generally do not cover the area of acute brain injury related to cardiovascular invasive procedures. In this international Consensus Statement, we compile the available knowledge (including data on prevalence, pathophysiology, risk factors, clinical presentation and management) to formulate consensus recommendations on the prevention, diagnosis and treatment of acute brain injury caused by cardiovascular interventions. We also identify knowledge gaps and possible future directions in clinical research into acute brain injury related to cardiovascular interventions., (© 2024. Springer Nature Limited.)

Colorectal cancer (CRC) is the second most common cause of cancer related deaths worldwide and the prevalence in young people especially is increasing annually. In the search for innovative approaches to treat the disease, drug delivery systems (DDS) are promising owing to their unique properties, which allow improved therapeutic results with lower drug concentrations, overcoming drug resistance and at the same time potentially reducing side effects. Silk fibroin is a biopolymer that can be processed to obtain biocompatible and biodegradable nanoparticles that can be efficiently loaded by surface adsorption with small-molecule therapeutics and allow their transport and sustained release by modulating their pharmacokinetics. Auranofin (AF) has recently been repurposed for its strong anticancer activity and is currently in clinical trials. Its mechanism of action is through the inhibition of thioredoxin reductase enzymes, which play an essential role in several intracellular processes and are overexpressed in some tumours. Taking into account that AF has a low solubility in water, we propose silk fibroin nanoparticles (SFN) as AF carrier in order to improve its bioavailability, increasing cellular absorption and preventing its degradation or avoiding some resistance mechanisms. Here we report the preparation and characterization of a new formulation of AF-loaded silk fibroin nanoparticles (SFN-AF), its functionalization with FITC for the analysis of cellular uptake, as well as its cytotoxic activity against cell lines of human colorectal cancer (HT29 and HCT116) in both 2D and 3D cell cultures. 3D spheroid models provide a 3D environment which mimics the 3D aspects of CRC observed in vivo and represents an effective 3D environment to screen therapeutics for the treatment of CRC. The loaded nanoparticles showed a spherical morphology with a hydrodynamic diameter of ~ 160 nm and good stability in aqueous solution due to their negative surface charges. FESEM-EDX analysis revealed a homogeneous distribution of Au clusters with high electron density on the surface of the nanoparticles. SFN-AF incubated in phosphate buffer at 37 °C released 77% of the loaded AF over 10 days, showing an initial burst and then sustained release. Flow cytometry analysis showed that FITC-SFN-AF was efficiently internalized by both cell lines, which was confirmed by confocal microscopy imaging. SFN enhanced the cytotoxicity of AF in 2D cultures in both CRC lines. Promising results were also obtained in 3D culture paving the way for future application of this strategy as a therapy for CRC., (© 2024. Controlled Release Society.)

Measuring pre-diagnostic blood metabolites may help identify novel risk factors for prostate cancer. Using data from 4387 matched case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we investigated the associations of 148 individual metabolites and three previously defined metabolite patterns with prostate cancer risk. Metabolites were measured by liquid chromatography-mass spectrometry. Multivariable-adjusted conditional logistic regression was used to estimate the odds ratio per standard deviation increase in log metabolite concentration and metabolite patterns (OR1SD) for prostate cancer overall, and for advanced, high-grade, aggressive. We corrected for multiple testing using the Benjamini-Hochberg method. Overall, there were no associations between specific metabolites or metabolite patterns and overall, aggressive, or high-grade prostate cancer that passed the multiple testing threshold (padj <0.05). Six phosphatidylcholines (PCs) were inversely associated with advanced prostate cancer diagnosed at or within 10 years of blood collection. metabolite patterns 1 (64 PCs and three hydroxysphingomyelins) and 2 (two acylcarnitines, glutamate, ornithine, and taurine) were also inversely associated with advanced prostate cancer; when stratified by follow-up time, these associations were observed for diagnoses at or within 10 years of recruitment (OR 1SD 0.80, 95% CI 0.66-0.96 and 0.76, 0.59-0.97, respectively) but were weaker after longer follow-up (0.95, 0.82-1.10 and 0.85, 0.67-1.06). Pattern 3 (8 lyso PCs) was associated with prostate cancer death (0.82, 0.68-0.98). Our results suggest that the plasma metabolite profile changes in response to the presence of prostate cancer up to a decade before detection of advanced-stage disease., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Associations of saturated and unsaturated fatty acids (FAs) with cardiovascular disease (CVD) remain controversial. We therefore aimed to investigate the prospective associations of objectively measured FAs with CVD, including incident coronary heart disease (CHD) and stroke, as well as CVD mortality., Methods: Circulating FA concentrations expressed as the percentage of total FAs were assayed in 172,891 participants without prior vascular disease at baseline from the European Prospective Investigation into Cancer and Nutrition-CVD (EPIC-CVD) (7,343 CHD; 6,499 stroke), UK Biobank (1,825; 1,474), and INTERVAL (285; 209) cohort studies. Hazard ratio (HR) per 1-standard deviation (SD) higher FA concentrations was estimated using Cox regression models and pooled by random-effects meta-analysis. Systematic reviews with meta-analysis published by 6 May 2023 on associations between FAs and CVDs were systematically searched and updated meta-analyses using random-effects model were conducted. Evidence from randomized controlled trials (RCTs) was also summarized., Results: Higher concentrations of total saturated FAs (SFAs) were associated with higher cardiovascular risks in the combined analysis, with differential findings noted for SFA subtypes in further analysis restricted to EPIC-CVD: positive associations for even-chain SFA [HR for CHD 1.24 (95% CI: 1.18-1.32); stroke 1.23 (1.10-1.38)] and negative associations for odd-chain [0.82 (0.76-0.87); 0.73 (0.67-0.78)] and longer-chain [0.95 (0.80-1.12); 0.84 (0.72-0.99)] SFA. In the combined analysis, total n-3 polyunsaturated FA (PUFA) [0.91 (0.85-0.97)], including docosahexaenoic acid (DHA) [0.91 (0.84-0.98)], was negatively associated with incident CHD risk. Similarly, total n-6 PUFA [0.94 (0.91-0.98)], including linoleic acid (LA) [0.89 (0.83-0.95)], was negatively associated with incident stroke risk. By contrast, more detailed analyses in EPIC-CVD revealed that several downstream n-6 PUFAs of LA were positively associated with CHD risk. Updated meta-analyses of 37 FAs including 49 non-overlapping studies, involving between 7,787 to 22,802 CHD and 6,499 to 14,221 stroke cases, showed broadly similar results as our combined empirical analysis and further suggested significant inverse associations of individual long-chain n-3 PUFAs and LA on both CHD and stroke. The findings of long-chain n-3 PUFAs were consistent with those from published RCTs on CHD despite insufficient evidence in monotherapy, while RCT evidence remained unclear for the rest of the explored FAs., Conclusions: Our study provides an overview of the most recent evidence on the associations between objectively measured FAs and CVD outcomes. Collectively, the data reveals notable differences in associations by SFA subtypes and calls for further studies, especially RCTs, to explore these links., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations ( BAZ2B and DDIAS ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research., Competing Interests: SD, RC, AL, JL, Md, IQ, RG, VN, MP, JT, JN, JA, CA, SA, VA, BA, NA, ÁA, EA, CA, MA, MA, RB, MB, MB, JB, MB, LB, MB, RB, MB, EC, CC, LC, JC, RC, MC, JC, MC, MD, AD, Vd, Ad, ED, RE, MF, MF, UF, AF, TF, MG, BG, JG, BÁ, FB, AG, JG, JG, MH, AH, MJ, ML, AB, RL, EM, CM, VM, OM, IM, MM, AM, JM, EM, PM, VC, SO, EO, MP, EP, NS, PP, PP, MP, TP, MP, GP, EP, GP, AP, SL, SR, MF, ER, FR, JR, FR, JR, PR, JS, JS, ET, AT, JT, AT, LT, MU, JV, ZY, RZ, Id, AR, PS, LR, EG, CA, EP, JR, AR, CF, PL, ÁC No competing interests declared, (© 2024, Diz-de Almeida, Cruz et al.)

Purpose: Investigate genetic and environmental influences on refractive errors in monozygotic (MZ) and dizygotic (DZ) twin pairs., Methods: We assessed foveal and peripheral refractions in 54 MZ and 46 DZ twins, capturing three scans across the retina. The study focused on spherical equivalent (M) at the fovea (MLOS) and changes in midperipheral (δMmid-periphery), and peripheral (δMperiphery) defocus, along with nasal-temporal asymmetry (root mean squared error [RMSEASY]) and image shell contour (RMSEAVG). Genetic and environmental contributions were analyzed using structural equation models., Results: No significant differences were observed between MZ and DZ twins for the examined variables. Intraclass correlations (ICC) indicated an important difference in genetic influence between MLOS, with the MZ twin pairs showing a higher correlation (0.83) than DZ (0.69) pairs, and δMperiphery, because the ICC for the MZ doubled (0.87) that of the DZ (0.42) pairs. Heritability estimates from the ACE model confirmed the large difference on genetic factors' influence on the variance for MLOS (0.13) and δMperiphery (0.77) change in refractive error. RMSEASY and RMSEAVG metrics showed significant genetic impact, particularly pronounced in the peripheral measurements, revealing high genetic control., Conclusions: The study delineates a marked environmental impact on central refractive errors, whereas genetic factors had a more significant influence on peripheral refractive variance and retinal image traits. Findings of the ACE model highlight the intricate genetic and environmental interplay in refractive error development, with a notable genetic dominance in peripheral vision characteristics. This suggests potential genetic targets for interventions in myopia management and emphasizes the need for personalized approaches based on genetic predispositions., Translational Relevance: Understanding the impact of genetics and environment on peripheral refraction is essential for deepening our fundamental knowledge of myopia and guiding the development of advanced myopia control strategies.

Background: Addiction to smartphone is defined as the disability to cease using the device despite the physical, psychological, or social consequences. The diagnosis of this disorder is increasing exponentially among teenagers, even more so after Corona Virus Disease 2019 (COVID-19) pandemic. This study aims to analyze the risk of mobile phone addiction among teenagers in Italy and its relationship with other risk behaviors, such as drug consumption and emotional well-being, following the COVID-19 pandemic., Methods: A cross-sectional observational study was conducted in Catania, Sicily, during 2022. The study sample comprised 342 students from a secondary education center that answered to a validated Italian version of the Smartphone Addiction Scale Short Version (SAS-SV) accessing through computers and mobile devices. Subjective Wellbeing was measured with the Personal Wellbeing Index-School Children (PWI-SC). Also, they completed the NIAAA Brief Alcohol Use Screener., Results: Our results showed that 30.1% of students who participated in the survey were classified with a smartphone addiction. Besides, most of the participants used the Smartphone for social networks (86.0%). Regarding the other aspects measured, the mean self-perceived well-being score measured with the PWI-SC was 55.5, and 36.2% of participants were categorized as "high risk" for depression. Finally, four out of ten participants were at "moderate or high risk" of an alcohol use disorder., Conclusions: Our results suggest that the use of mobile phones is increasing in adolescents, an age group also exposed to social and health problems.

Nanotechnology and its applications have advanced significantly in recent decades, contributing to various fields, including reproduction. This study introduces a novel method to label porcine oocytes with nanoparticles (NPs) bound to oviductin (OVGP1, Ov) for use in Assisted Reproductive Technologies (ARTs). Despite promising developments, concerns about NP toxicity in gametes necessitate thorough investigation. This research aims to assess the impact of functionalized NPs (NPOv) on sperm functionality. Boar sperm were co-incubated with NPOv for 0, 0.5 and 1 h in two media: BTS (semen dilution and conservation) and TALP (sperm capacitation and in vitro fertilization-IVF). Sperm quality parameters (viability, motility and kinematics) showed no significant differences in TALP medium (p > .05). In BTS, although some kinetic parameters were altered, motility, progressive motility and viability remained unaffected (p > .05). Additionally, NPs presence on the zona pellucida (ZP) of oocytes did not affect sperm attachment (p > .05). In conclusion, in vitro exposure of boar sperm to OVGP1-functionalized NPs in IVF medium or attached to the ZP surface of matured oocytes does not impair sperm functionality, including their binding ability to the ZP., (© 2024 The Author(s). Reproduction in Domestic Animals published by Wiley‐VCH GmbH.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In multiple myeloma (MM), measurable residual disease (MRD) is assessed in bone marrow (BM). However, less invasive evaluation of peripheral residual disease (PRD) in blood could be advantageous and less cumbersome. We investigated the prognostic value of PRD monitoring after 24 cycles of maintenance in 138 transplant-eligible patients with MM enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials. PRD was assessed using next-generation flow (NGF) and mass spectrometry (MS). Positive PRD by NGF in 16/138 (11.5%) patients was associated with a 13-fold increased risk of progression and/or death; median progression-free survival (PFS) and overall survival (OS) were 2.5 and 47 months, respectively. Considering patients' MRD status in BM as the reference, PRD detection using NGF showed positive and negative predictive values of 100% and 73%, respectively. Presence of PRD helped identifying patients at risk of imminent progression among those with positive MRD in BM. Patients with undetectable PRD according to both NGF and MS showed 2-year PFS and OS rates of 97% and 100%, respectively. In multivariate analyses including the Revised International Staging System and the complete remission status, only MRD in BM and PRD by NGF showed independent prognostic value for PFS. This study supports the use of less invasive PRD monitoring during maintenance or observation in transplant-eligible patients with MM.

Background: The Otago Exercise Programme is an effective intervention for falls prevention. However, there is limited evidence in relation to studies that compare efficacy for falls prevention when delivered Otago Exercise Programme in a group or individual format in a primary care context., Objective: To compare the Otago Exercise Programme delivered as a group vs. individual format for community dwelling older adults, over a one year period. The hypothesis was that neither format would be inferior to the other., Methods: DESIGN: A four-year multicentre, randomized, non-inferiority clinical trial, with two arms- Otago Exercise Programme group training and individual Otago exercise training., Setting(s): 21 primary healthcare centers., Participants: A sample size of 728 participants was established. Participants were aged between 65 and 80 years; living in the community; able to walk independently; and agreed to take part in the study and provided signed informed consent., Intervention: The Otago Exercise Programme was delivered mainly by nurses in primary care, with five face to face sessions, and a reinforcement 6 months later. Participants were encouraged to exercise at home between face to face sessions., Data Collection: at baseline and after 6 and 12 months from October 2017 to 2020., Primary Outcome: people who reported at least one fall., Secondary Outcomes: number of falls, cause of falls, consequences and assistance, adherence and satisfaction. Group allocation was blinded to the researchers involved in analysis. Reporting: Consolidated Standards of Reporting Trials recommendations for the Statement for Randomized Trials of Nonpharmacologic Treatments., Results: Eight hundred twenty-seven participants were randomized (226 were allocated in group training and 272 in individual training). The analysis of the proportion of people who reported at least one fall and number of falls showed no differences between individual and group training. Assessment of the equivalence between the interventions at 12 months showed that the confidence interval for the difference of people who reported at least one fall was found to be within the equivalence limit of 10% considered. However, in those participants with a previous history of falls, group format showed potentially greater benefit. The participants in individual training presented higher scores on the Exercise Adherence Rating Scale test. No differences were found in satisfaction between the groups., Conclusions: The group Otago Exercise Programme is equivalent to individually delivered Otago Exercise Programme in terms of prevention of falls over a 12-month follow up. Adherence was higher in individual training., Implications: Healthcare professionals could offer either Otago Exercise Programme format dependent on patient preference and be confident that that standardized intervention provides patient benefit., Trial Registration: ClinicalTrials.gov (NCT03320668). Data registration 31/10/2017., (© 2024. The Author(s).)

Background: Some clinical characteristics and comorbidities in atrial fibrillation (AF) patients are exclusion criteria in randomized clinical trials (RCTs) investigating oral anticoagulants (OAC). However, these conditions are present also in everyday clinical practice patients. We compared the risk of adverse clinical outcomes between patients with and without RCT exclusion criteria., Methods: The Murcia AF Project II was an observational cohort study including AF outpatients starting vitamin K antagonists (VKAs) from July 2016 to June 2018. For the selection of the exclusion criteria, the four pivotal RCTs of direct-acting OAC (DOACs) were used as reference. During 2 years, all ischemic strokes/transient ischemic attacks, major adverse cardiovascular events (MACEs), major bleeds, and all-cause deaths were recorded., Results: 1050 patients (51.5% female, median age 77 years) were included, of whom 368 (35%) met at least one exclusion criterion for RCTs. During follow-up, the incidence rate ratios for major bleeding, MACE and all-cause mortality were higher among patients with exclusion criteria (all p < 0.001). Patients fulfilling at least one exclusion criterion had increased risks of major bleeding (aHR 1.48; 95% CI 1.22-1.81; p < 0.001), MACE (aHR 1.51, 95% CI 1.10-2.09, p = 0.012), and mortality (aHR 3.22, 95% CI 2.32-4.48, p < 0.001), as well as a lower event-free survival (all log-rank p < 0.001)., Conclusions: In this AF cohort taking VKAs, more than one-third had at least one RCT exclusion criteria, which translates into higher risk of major bleeding, MACE, and death. These observations should be considered when translating RCTs results to AF patients for a proper and a more patient-centered management., (© 2024. The Author(s).)

Livestock management is evolving into a new era, characterized by the analysis of vast quantities of data (Big Data) collected from both traditional breeding methods and new technologies such as sensors, automated monitoring system, and advanced analytics. Artificial intelligence (A-In), which refers to the capability of machines to mimic human intelligence, including subfields like machine learning and deep learning, is playing a pivotal role in this transformation. A wide array of A-In techniques, successfully employed in various industrial and scientific contexts, are now being integrated into mainstream livestock management practices. In the case of swine breeding, while traditional methods have yielded considerable success, the increasing amount of information requires the adoption of new technologies such as A-In to drive productivity, enhance animal welfare, and reduce environmental impact. Current findings suggest that these techniques have the potential to match or exceed the performance of traditional methods, often being more scalable in terms of efficiency and sustainability within the breeding industry. This review provides insights into the application of A-In in porcine breeding, from the perspectives of both sows (including welfare and reproductive management) and boars (including semen quality and health), and explores new approaches which are already being applied in other species., Competing Interests: Declaration of Competing Interest The author (FRANCISCO A. GARCÍA VÁZQUEZ) declares no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction and Objectives: Stroke and bleeding risks in atrial fibrillation (AF) are often assessed at baseline to predict outcomes years later. We investigated whether dynamic changes in CHA 2 DS 2 -VASc and HAS-BLED scores over time modify risk prediction., Methods: We included patients with AF who were stable while taking vitamin K antagonists. During a 6-year follow-up, all ischemic strokes/transient ischemic attacks (TIAs) and major bleeding events were recorded. CHA 2 DS 2 -VASc and HAS-BLED were recalculated every 2-years and tested for clinical outcomes at 2-year periods., Results: We included 1361 patients (mean CHA 2 DS 2 -VASc and HAS-BLED 4.0±1.7 and 2.9±1.2). During the follow-up, 156 (11.5%) patients had an ischemic stroke/TIA and 269 (19.8%) had a major bleeding event. Compared with the baseline CHA 2 DS 2 -VASc, the CHA 2 DS 2 -VASc recalculated at 2 years had higher predictive ability for ischemic stroke/TIA during the period from 2 to 4 years. Integrated discrimination improvement (IDI) and net reclassification improvement (NRI) showed improvements in sensitivity and better reclassification. The CHA 2 DS 2 -VASc recalculated at 4 years had better predictive performance than the baseline CHA 2 DS 2 -VASc during the period from 4 to 6 years, with an improvement in IDI and an enhancement of the reclassification. The recalculated HAS-BLED at 2-years had higher predictive ability than the baseline score for major bleeding during the period from 2 to 4 years, with significant improvements in sensitivity and reclassification. A slight enhancement in sensitivity was observed with the HAS-BLED score recalculated at 4 years compared with the baseline score., Conclusions: In AF patients, stroke and bleeding risks are dynamic and change over time. The CHA 2 DS 2 -VASc and HAS-BLED scores should be regularly reassessed, particularly for accurate stroke risk prediction., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: People with secondary progressive multiple sclerosis (pwSPMS) experience increasing disability, which impacts negatively on their health-related quality of life (HRQoL). Our aims were to assess the impact of secondary progressive multiple sclerosis (SPMS) on functional status and HRQoL and describe the clinical profile in this population., Methods: DISCOVER is an observational, cross-sectional, multicenter study with retrospective data collection in real-world clinical practice in Spain. Sociodemographic and clinical variables, functional and cognitive scales, patient-reported outcomes (PROs), and direct healthcare, and non-healthcare and indirect costs were collected., Results: A total of 297 evaluable pwSPMS with a EDSS score between 3-6.5 participated: 62.3 % were female and 18.9 % had active SPMS. At the study visit, 77 % of them presented an Expanded Disability Scale Score (EDSS) of 6-6.5. Nearly 40 % did not receive any disease-modifying treatment. Regarding the working situation, 61.6 % were inactive due to disability. PROs: 99.3 % showed mobility impairment in EuroQoL-5 Dimensions-5 Levels, and about 60 % reported physical impact on the Multiple Sclerosis Impact Scale-29. Fatigue was present in 76.1 %, and almost 40 % reported anxiety or depression. The Symbol Digit Modalities Test was used to assess cognitive impairment; 80 % of the patients were below the mean score. Participants who presented relapses two years before and had high EDSS scores had a more negative impact on HRQoL. PwSPMS with a negative impact on HRQoL presented a higher cost burden, primarily due to indirect costs., Conclusions: PwSPMS experience a negative impact on their HRQoL, with a high physical impact, fatigue, cognitive impairment, and a high burden of indirect costs., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier B.V.)

Background: In recent years, there has been growing interest in laparoscopic liver resection (LLR) and the audit of the results of surgical procedures. The aim of this study was to define reference values for LLR in segments 7 and 8., Study Design: Data on LLR in segments 7 and 8 between January 2000 and December 2020 were collected from 19 expert centers. Reference cases were defined as no previous hepatectomy, American Society of Anesthesiologists score less than 3, BMI less than 35 kg/m 2 , no chronic kidney disease, no cirrhosis and portal hypertension, no COPD (forced expiratory volume 1 <80%), and no cardiac disease. Reference values were obtained from the 75th percentile of the medians of all reference centers., Results: Of 585 patients, 461 (78.8%) met the reference criteria. The overall complication rate was 27.5% (6% were Clavien-Dindo 3a or more) with a mean Comprehensive Complication Index of 7.5 ± 16.5. At 90-day follow-up, the reference values for overall complication were 31%, Clavien-Dindo 3a or more was 7.4%, conversion was 4.4%, hospital stay was less than 6 days, and readmission rate was <8.33%. Patients from Eastern centers categorized as low risk had a lower rate of overall complication (20.9% vs 31.2%, p = 0.01) with similar Clavien-Dindo 3a or more (5.5% and 4.8%, p = 0.83) compared with patients from Western centers, respectively., Conclusions: This study shows the need to establish standards for the postoperative outcomes in LLR based on the complexity of the resection and the location of the lesions., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

HSP47, a chaperone whose main function is the maturation of collagen molecules, is considered a marker of fibrotic diseases. Increased collagen synthesis in the testis has been associated with various pathologies leading to seminiferous tubule regression. Our aim was to study whether HSP47 is expressed in hamster Sertoli cells both in the adult and in two physiological situations of seminiferous tubule atrophy: irreversible testicular ageing and testicular regression due to short photoperiod (reversible). Eighteen animals were divided as follows: a group of 6 young animals aged 6 months, a group of 6 animals aged 24 months, which were exposed to a long photoperiod, and a final group of 6 young animals subjected to a short photoperiod. Testicular samples were fixed in methacarn and an immunohistochemical technique was used to detect HSP47. A semiquantitative study of of this protein expresion was performed between tubular sections of aged animals with complete spermatogenesis and arrested spermatogenesis and tubular sections with arrest spermatogenesis of photoinhibited testes. Sertoli cells were positive for HSP47, the intensity being greater in tubular sections with arrested spermatogenesis in both aged and photoinhibited animals. Semiquantitative analysis corroborated this observation in the sense that the expression of this protein differed according to the functional state of the seminiferous tubules. Thus, the radio of immunoreactivity was significantly higher in tubular sections with arrested spermatogenesis in aged animals compared with regressed animals, and in the latter compared with those whose tubular sections showed complete spermatogenesis. In conclusion, HSP47 expression in Sertoli cells was found for the first time in mammals. Moreover, increased expression seemed to be related to the degree of atrophy of the seminiferous epithelium and to the reversible or non-reversible physiological state of the seminiferous epithelium., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

The impact of tumor-infiltrating B cells on breast cancer (BRCA) outcomes remains poorly understood. Recent findings from Yang et al. identify an atypical, clonally expanded population of activated Fc receptor-like 4 (FCRL4) + B cells that is associated with improved overall survival in patients affected by various tumor types, including BRCA., Competing Interests: Declaration of interests L.G. is holding/has held research contracts with Lytix Biopharma, Promontory, and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, AbbVie, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. The other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Rondaptivon pegol (previously BT200) is a pegylated RNA aptamer that binds to the A1 domain of von Willebrand factor (VWF). Recent clinical trials demonstrated that BT200 significantly increased plasma VWF-factor VIII levels by attenuating VWF clearance. The biological mechanism(s) through which BT200 attenuates in vivo clearance of VWF has not been defined. We hypothesized that BT200 interaction with the VWF-A1 domain may increase plasma VWF levels by attenuating macrophage-mediated clearance. We observed that full-length and VWF-A1A2A3 binding to macrophages and VWF-A1 domain binding to lipoprotein receptor-related protein 1 (LRP1) cluster II and cluster IV were concentration-dependently inhibited by BT200. Additionally, full-length VWF binding to LRP1 expressed on HEK293T (HEK-LRP1) cells was also inhibited by BT200. Importantly, BT200 interacts with the VWF-A1 domain in proximity to a conserved cluster of 4 lysine residues (K1405, K1406, K1407, and K1408). Alanine mutagenesis of this K1405-K1408 cluster (VWF-4A) significantly (P < .001) attenuated binding of VWF to both LRP1 clusters II and IV. Furthermore, in vivo clearance of VWF-4A was significantly (P < .001) reduced than that of wild-type VWF. BT200 did not significantly inhibit binding of VWF-4A to LRP1 cluster IV or HEK-LRP1 cells. Finally, BT200 interaction with the VWF-A1 domain also inhibited binding to macrophage galactose lectin and the SR-AI scavenger receptor. Collectively, our findings demonstrate that BT200 prolongs VWF half-life by attenuating macrophage-mediated clearance and specifically the interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1. These data support the concept that targeted inhibition of VWF clearance pathways represents a novel therapeutic approach for von Willebrand disease and hemophilia A., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The aim of our study is to evaluate the relationship between sociodemographic and clinical characteristics of individuals with Colorectal Cancer (CRC), tumour-intrinsic characteristics and treatment received with health-related quality of life (HRQoL)., Methods: Cross-sectional analysis of data from 805 survivors from the MCC study was conducted. HRQoL was assessed through a general and specific questionnaire, SF-12 and FCSI (Colorectal Symptom Index). Statistical analyses were performed with linear regression with adjustment for sociodemographic variables, stage at diagnosis and histological grade., Results: Participants had survived a median of 7.9 years from diagnosis (IQR 7.1-8.5 years). Age at diagnosis, sex and area showed a clear association with HRQoL in both physical and mental dimensions of the SF-12 questionnaire. A direct association between CRC recurrence was also found in the PCS-12 and MCS-12 dimensions and radical surgery in the PCS-12. Regarding the scores in FCSI questionnaire, statistically significant differences were observed by sex, age and area, with older women being the most impaired ( p < 0.001)., Conclusions: Age, sex and area was associated with lower scores of HRQoL among CRC survivors. Knowing the determinants related to HRQoL would allow us to lay the groundwork to develop strategies that help reduce morbidity and mortality, relapses and increase HRQoL.

Background and Objectives: The 2023 criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) perform well in adults but have not been assessed in children., Methods: This prospective observational nationwide study includes children and adults with demyelinating syndromes or encephalitis, whose serum or CSF was found MOG-immunoglobulin G (IgG) positive at Institut d'Investigacions Biomèdiques August Pi i Sunyer-Hospital Clínic of Barcelona (Spain). Exclusion criteria were lack of clinical information and follow-up <1 year, and serum unavailable for antibody testing. The primary outcome was to assess the accuracy of the 2023 MOGAD criteria, using as gold standard the most plausible diagnosis after a follow-up >1 year. MOGAD criteria were retrospectively applied assessing core syndromes, supportive clinical-radiological features, and MOG-IgG titers. Patients tested ≤3 months of a disease attack (acute phase) or afterward (remission) were considered separately. The positive predictive value (PPV) of the criteria (true-positive [patients classified as MOGAD and MOGAD diagnosis last follow-up] divided by total positive [all patients classified as MOGAD]), and its 95% CI, was calculated with the Wilson procedure., Results: A total of 257 patients (133 children) were included in the study (median age 15 years [interquartile range 6-38], 54% female). Among 202 patients assessed during a disease attack, 158 (78%) had high MOG-IgG serum titers, 36 (18%) low titers, and 8 (4%) antibodies only in CSF. No differences were identified between patients with high and low titers, but those with low titers were more likely to have an alternative diagnosis at last follow-up (2/36 [6%] vs 0/158, p = 0.012). Supportive features were present in 230 of 257 (89%) patients, regardless of age, MOG-IgG titers, and core syndromes except for optic neuritis in adults whose assessment with orbital MRI was not systematic. Overall, 240 of 257 (94%) patients were well classified by the MOGAD criteria (e.g., 236 eventually having MOGAD and 4 alternative diagnoses), and 17 were wrongly classified (e.g., 11 eventually having MOGAD and 6 alternative diagnoses). Although the criteria classified better during disease attacks than during remissions (187 [96%] vs 49 [89%] serum MOG-IgG-positive patients were well-classified, p = 0.038), the PPV was high in both settings (99% [95% CI 97-100] vs 98% [95% CI 89-100])., Discussion: The 2023 MOGAD criteria correctly identified most children and adults with MOGAD. The highest accuracy occurred when they were applied during disease attacks., Classification of Evidence: This study provides Class IV evidence that the 2023 MOGAD criteria accurately identify adults and children with MOGAD.

Objective: This meta-analysis aims to quantitatively summarize current data on various potential risk factors of velamentous cord insertion (VCI). A better understanding of these risk factors could enhance prenatal identification both in settings with routine screening and in those where universal screening for cord insertion anomalies is not yet recommended. Methods: A systematic search was conducted in MEDLINE, Cochrane Library, and Scopus from their inception until 7 February 2024. Eligible studies included observational studies of singleton pregnancies with VCI, identified either prenatally or postnatally, compared with pregnancies with central or eccentric cord insertion. Analyses were performed using DerSimonian and Laird random-effects models, with outcomes reported as risk ratios (RR) or mean differences with 95% confidence intervals (CI). Results: In total, 14 cohort and 4 case-control studies were included, reporting on 952,163 singleton pregnancies. Based on the cohort studies, the overall prevalence of VCI among singleton pregnancies was calculated to be 1.54%. The risk of VCI was significantly higher among pregnancies conceived using assisted reproductive technology (RR, 2.32; 95% CI: 1.77-3.05), nulliparous women (RR, 1.21; 95% CI: 1.15-1.28), women who smoked (RR, 1.14; 95% CI: 1.08-1.19), and pregnancies diagnosed with placenta previa (RR, 3.60; 95% CI: 3.04-4.28). Conclusions: This meta-analysis identified assisted reproductive technology, nulliparity, smoking, and placenta previa as significant risk factors of VCI among singleton pregnancies. These findings could inform screening policies in settings where universal screening for cord insertion is not routinely performed, suggesting a targeted approach for women with these specific risk factors.

Coffee pulp is a by-product characterized by its richness in phenolic compounds. This study examined the catabolism of (poly)phenols in digested coffee pulp flour (CPF) and extract (CPE) during in vitro colonic fermentation. After a simulated gastrointestinal digestion, samples were fermented using human microbiota and (poly)phenol transformations were analyzed by UHPLC-ESI-MS/MS. Digested CPF and CPE contained high amounts of phenolic acids, notably 3',4'-dihydroxycinnamic (99.7-240.1 μmol 100 g -1 ) and 3,4-dihydroxybenzoic acid (174.1-491.4 μmol 100 g -1 ). During the in vitro fecal fermentation, phenylpropanoic acids (1.5- to 2.6-fold), phenyl-γ-valerolactones (1.3- to 23-fold), phenylvaleric acids (1.1- to 2-fold) and benzene derivatives (1.5-fold) increased; while benzoic and cinnamic acids, cinnamoylquinic derivatives, flavonols, benzaldehydes and diphenylpropan-2-ols decreased. The (poly)phenols in CPF were catabolized more slowly than in CPE, suggesting protection of the fibrous matrix against phenolic degradation. Coffee pulp may be a promising food ingredient rich in (poly)phenols contributing to the prevention of intestinal diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction and Objectives: By 2022, 9 centers had been accredited by the Spanish Society of Cardiology for the atrial fibrillation (AF) process. Our objective was to evaluate the performance of these centers based on the quality indicators (QIs) proposed by the European Society of Cardiology (ESC) in 2020., Methods: Adults with AF who were attended in the cardiology departments of participating centers during the second week of May 2019 were included in a retrospective registry (n=797, age 72±11 years, 60% male). Key ESC QIs were assessed., Results: CHA 2 DS 2 -VASc, HAS-BLED scores, and serum creatinine levels were documented in 24.9%, 6.1%, and 96.2% of patients, respectively. Anticoagulation was appropriately prescribed in 90.6% of high-risk patients according to the CHA 2 DS 2 -VASc score, but was inappropriately prescribed in 57.8% of low-risk patients. Among all patients, 84.1% received high-quality anticoagulation. Inappropriate antiarrhythmic drugs were prescribed in 7.2% of patients with permanent AF, 2.9% of those with structural heart disease, and 0.0% of those with end-stage kidney disease. Catheter ablation was offered to 70% of patients with symptomatic paroxysmal or persistent AF after the failure or intolerance of 1 antiarrhythmic drug. All modifiable risk factors were documented in 59.3% of patients. Rates of all-cause mortality, ischemic stroke or transient ischemic attack, and major bleeding were 8.1, 0.8, and 2.56 per 100 patients/y, respectively. QIs for anticoagulation and outcomes were similar between general cardiology and tertiary referral centers., Conclusions: Although accredited centers in Spain demonstrated good performance in many of the ESC QIs for AF, there remains room for improvement. These data could serve as a starting point for enhancing the quality of care in this population., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

This study examined how the vitrification of pig blastocysts using either the superfine open pulled straw (SOPS) or Cryotop method affects the expression profile of embryonic microRNA (miRNA) transcriptomes, as well as its relation to changes in the expression of target genes (TGs). Surgically collected pig blastocysts were vitrified using either the SOPS method (n = 60; 4-6 embryos/device) or the Cryotop system (n = 60; 20 embryos/device). Embryos were cultured in vitro for 24 h after warming. Fresh blastocysts (n = 60) cultured for 24 h served as controls. After in vitro culture, five pools of eight viable blastocysts from each group were prepared for miRNA expression analysis based on a microarray approach. Then, biological interpretation of miRNAs profiles and integrative analysis of miRNA and mRNA transcriptome data were performed. Survival after 24 h of in vitro culture was similar (>96 %) for both the vitrification systems and the control group (100 %). Compared with the controls, the SOPS-vitrified blastocysts had 94 (one upregulated and 93 downregulated) differentially expressed (DE) miRNAs, and the Cryotop-vitrified blastocysts had 174 DE miRNAs (one upregulated and 173 downregulated). One DE miRNA (miR-503) in the SOPS group and three DE miRNAs (miR-7139-3p, miR-214 and miR-885-3p) in the Cryotop group were annotated for Sus scrofa. The integrative analysis showed that 27 and 61 DE TGs were regulated by the DE miRNAs in blastocysts vitrified with the SOPS and Cryotop systems, respectively. The TGs enriched one pathway (the TGF-β signaling pathway) for the SOPS system and four pathways (HIF-1, Notch, ascorbate and aldarate metabolism and glycosphingolipid biosynthesis-ganglio series) for the Cryotop system. In summary, vitrification via the SOPS and Cryotop systems dysregulates miRNAs, with slight differences between methods. The altered miRNAs identified in this study were related mainly to cell proliferation, apoptosis, and the response to cell stress. Further studies are needed to clarify the consequences of dysregulation of miRNAs involved in the TGF-β (SOPS-vitrified blastocyst) and Notch (Cryotop-vitrified blastocyst) signaling pathways, particularly if they can affect embryonic development., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartially of the research reported., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Exposure to pesticides, poses a significant threat to male fertility by compromising crucial cells involved in spermatogenesis. Aminocarb, is a widely used carbamate insecticide, although its detrimental effects on the male reproductive system, especially on sustentacular Sertoli cells, pivotal for spermatogenesis, remains poorly understood. In this study, we investigated the effects of escalating concentrations of aminocarb on a mouse Sertoli cell line, TM4. Assessments included cytotoxic analysis, mitochondrial biogenesis and membrane potential, expression of apoptotic proteins, caspase-3 activity, and oxidative stress evaluation. Our findings revealed a dose-dependent reduction in the proliferation and viability of TM4 cells following exposure to increasing concentrations of aminocarb. Notably, exposure to 5 μM of aminocarb induced depolarization of mitochondria membrane potential, and a significant decrease in the ratio of phosphorylated eIF2α to total eIF2α, suggesting heightened endoplasmic reticulum stress via the activation of the eIF2α pathway. Moreover, the same aminocarb concentration was demonstrated to increase both caspase-3 protein levels and activity, indicating an apoptotic induction. Collectively, our results demonstrate that aminocarb serves as an apoptotic inducer for mouse sustentacular Sertoli cells in vitro, suggesting its potential to modulate independent pathways of the apoptotic cascade. These findings underscore the deleterious impact of aminocarb on spermatogenic performance and male fertility, highlighting the urgent need for further investigation into its mechanisms of action and mitigation strategies to safeguard male fertility.

Infancy is a period of continuous growth and development, where inadequate intake of essential elements and exposure to non-essential elements may have lifelong health consequences. Thus, the aim of this study is to evaluate the urine concentration of essential and non-essential elements as a proxy for internal exposure during the weaning period, from 3 to 18 months of age. The Nutrition in Early Life and Asthma (NELA) birth cohort generated the data for this study. Sociodemographic, dietary, and urine concentration of essential (Co, Cu, Mo, I, Fe, Mn, Se, Zn, and Ni) and non-essential elements (Al, V, As, Cd, Sb, Tl, and Pb) data were available for 490 participants at 3 months of age and 216 participants at 18 months of age. Paired urine samples at both time periods were available for 175 infants. At 3 months of age, exclusively breastfed infants had lower urine concentrations of Al, V, Fe, Co, Se, Sb, and Tl. Notably, the concentration of Mo had a median (IQR) of 0.60 (0.40-2.10) μg/L compared to a median (IQR) of 39.80 (25.00-56.40) μg/L observed in infants exclusively fed with formula. When we analyzed the change in urine elements concentrations between 3 and 18 months of age, we observed increased As (0.75 vs. 18.60 μg/L), Co (0.05 vs. 0.24 μg/L), Mo (1.98 vs. 50.0 μg/L), Pb (0.15 vs. 0.69 μg/L), Se (11.3 vs. 23.1 μg/L), Tl (0.02 vs. 0.11 μg/L), and V (0.05 vs. 0.11 μg/L). For Cu, lower urine concentrations were observed at 18 months of age in comparison with concentrations at 3 months (5.77 vs. 4.41 μg/L). Among the main food items identified as driving the changes in urine concentration between 3 and 18 months of age were white fish, rice and pasta, potato chips, custard, small blue fish, and legumes. Exclusively breastfed infants showed lower exposure to non-essential elements compared to those who were fed with a mixture or formula. With the introduction of solid foods, the exposure to some non-essential elements increased drastically, as in the case of As and Pb. In addition, exposure to the essential metal Mo also increased substantially with the introduction of solid food., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AJ Signes Pastor reports financial support was provided by Generalitat Valenciana. AJ Signes Pastor reports financial support was provided by Carlos III Health Institute. Jesus Vioque reports financial support was provided by Carlos III Health Institute. Eva Morales reports financial support was provided by Spanish Ministry of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The Barcelona Clinic Liver Cancer (BCLC) staging schema is widely used for hepatocellular carcinoma (HCC) treatment. In the updated recommendations, HCC BCLC stage B can become candidates for transplantation. In contrast, hepatectomy is currently not recommended., Methods: This systematic review includes a multi-institutional meta-analysis of patient-level data. Survival, postoperative mortality, morbidity and patient selection criteria for liver resection and transplantation in BCLC stage B are explored. All clinical studies reporting HCC patients with BCLC stage B undergoing liver resection or transplantation were included., Results: A total of 31 studies with 3163 patients were included. Patient level data was available for 580 patients from 9 studies (423 after resection and 157 after transplantation). The overall survival following resection was 50 months and recurrence-free survival was 15 months. Overall survival after transplantation was not reached and recurrence-free survival was 45 months. The major complication rate after resection was 0.11 (95%-CI, 0.0-0.17) with the 90-day mortality rate of 0.03 (95%-CI, 0.03-0.08). Child-Pugh A (93%), minor resection (60%), alpha protein level less than 400 (64%) were common in resected patients. Resected patients were mostly outside the Milan criteria (99%) with mean tumour number of 2.9. Studies reporting liver transplantation in BCLC stage B were scarce., Conclusion: Liver resection can be performed safely in selected patients with HCC BCLC stage B, particularly if patients present with preserved liver function. No conclusion can done on liver transplantation due to scarcity of reported studies., (© 2024. The Author(s).)

Pig production, a vital sector of the meat industry, faces demands for improved quality, efficiency, and sustainability. Advancements in breeding, disease control, and artificial insemination have enhanced production, while biotechnologies such as in vitro embryo production (IVP) and genetic engineering offer further progress. In vitro embryo production could facilitate the global exchange of valuable genetic material, accelerate breeding programs, and improve productivity, and it is essential for generating genetically modified (GM) pigs. These GM pigs have two main applications: first, they allow for targeted modifications aimed at improving production traits relevant to pig production in agriculture, such as meat quality and disease resistance. Second, they serve as valuable biomedical models for human disease research, regenerative medicine, and organ transplantation. Yet, despite notable advancements in recent decades, the efficiency of the current IVP systems for porcine embryos remains a challenge. Compared to the in vivo environment, suboptimal culture conditions lead to issues such as elevated polyspermy, poor embryo development, and the production of low-quality blastocysts. This review provides an overview of the key steps and recent advancements in porcine IVP technology. We will emphasize the promising utilization of oocytes from live females of high genetic value through ovum pick-up and the incorporation of extracellular vesicles and cytokines into IVP media. These innovative strategies hold immense potential to significantly enhance embryo development and overall success rates in porcine IVP, and could open the door for significant progress in both agriculture and biomedicine applications., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The funders had no role in the design, writing, or in the decision to publish the manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Introduction and Objectives: Invasive management in frail patients with non-ST-segment elevation myocardial infarction (NSTEMI) remains controversial. We investigated the impact of various geriatric conditions., Methods: The MOSCA-FRAIL trial included 167 adults aged ≥ 70 years with frailty (Clinical Frailty Scale [CFS] ≥ 4 points) and NSTEMI, who were randomized to either an invasive (n=84) or conservative (n=83) strategy. In addition to frailty, we measured activities of daily living (Barthel index), cognitive impairment (Pfeiffer test), and comorbidities (Charlson index). The primary endpoint was the difference (invasive minus conservative) in restricted mean survival time (RMST) for all-cause mortality at a median follow-up of 3.9 years., Results: A total of 93 patients died. The RMST difference favored invasive management at the CFS 25th percentile (CFS=4; 157 days, 95%CI, 18-295; P=.027), which changed to a nonsignificant effect at the 50th and 75th percentiles. The RMST difference remained nonsignificant, irrespective of the severity of other geriatric assessments. In time-to-event analysis, invasive management was associated with an initially lower life expectancy, peaking at around 1 year, among all subgroups. However, patients with CFS=4 experienced a benefit at the end of follow-up (181 days, 95%CI, 19-343), whereas those with CFS >4 did not (-16 days, 95%CI, -217 to 186; interaction P=.16). Subgroups defined by other geriatric markers showed a similar time-dependent trend, albeit with weaker statistical interaction., Conclusions: Among adults with frailty and NSTEMI, the CFS might be useful for evaluating the relative risks and benefits of invasive management. A CFS >4 could serve as a valuable threshold for decision-making., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Statement of Problem: Interim fixed prostheses are used provisionally to provide esthetics and maintain function until placement of the definitive prosthesis. Polymethyl methacrylate (PMMA) has been widely used as an interim material but has mechanical limitations that can be improved with the addition of nanomaterials such as graphene fibers (PMMA-G). However, studies on the biocompatibility of this material are lacking., Purpose: The purpose of this in vitro study was to determine the biocompatibility and cytotoxic effects of PMMA compared with PMMA-G in periodontal ligament stem cells (PDLSCs) by measuring the viability and cell apoptosis of those cells subjected to different concentrations of both compounds by elution, as well as the surface characterization of these materials., Material and Methods: Sterile Ø20×15-mm specimens of PMMA and PMMA-G were covered with Dulbecco modified Eagle medium for 24 hours to be the subsequent eluent. PDLSCs were seeded in 6 plates of 96 wells at dilutions 1/1, 1/2, 1/4, and 1/8 for each material. Three plates for the cell viability assay with MTT and 3 plates for the cell apoptosis assay with Hoechst 33342 staining were used in turn to subdivide the measurements at 24, 48, and 72 hours. The Kruskal-Wallis test was used to compare the data obtained in the different dilutions at different times and the Mann-Whitney test to compare both materials. Topography and wetting were analyzed for surface characterization. The Student t test of paired measurements was used to compare the different surfaces for each parameter (α=.05 for all tests)., Results: In both the cell viability assay (MTT) and the cell apoptosis assay, the test did not identify statistically significant differences in PMMA and PMMA-G with respect to the control group in the different dilutions at different times (P>.05). When comparing both materials, no statistically significant differences (P=.268) were found in either trial. PMMA-G had lower roughness and kurtosis and higher wetting than PMMA., Conclusions: Both PMMA and PMMA-G were found to be biocompatible materials with no significant differences between them after cell viability and apoptosis testing. PMMA-G had higher wettability and lower roughness than PMMA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Scientists and coaches seek effective ergogenic aids for performance improvement. Cyclists commonly use β-Alanine, which may enhance post-exercise recovery and physical performance. High-dose β-Alanine supplementation's impact on World Tour cyclists during a 7-day camp remains unstudied. This study aimed to analyse the effect of a high dose of β-alanine in World Tour cyclist during a 7-day camp. A double-blinded, randomised controlled trial was conducted. 11 cyclists were included in the final analysis: β-alanine supplementation (n = 5; VO2max: 67.6±1.6 ml/kg/min) and a placebo group (n = 6; VO2max: 68.0±2.4 ml/kg/min). The duration of the supplementation protocol was seven days with four daily intakes. The subjects commenced supplementation after the physical tests (immediately following the snack) and consumed the final intake after breakfast on the day of the final test (a total of 7 days and 3 additional doses, 31 servings in total; 5g per dosage; 155g the total cumulative amount). Before and after seven days of supplementation, the cyclists performed an uphill time trial. Blood lactate, heart rate and rating of perceived exertion were measured during test. β-alanine supplementation improved the relative mean power attained during the time-trial compared with the control group (Z = -2.008; p = 0.045; Δ = 0.060), as well as the time needed to complete this trial (Z = -2.373; p = 0.018). As for physiological and metabolic variables, no significant change was found. In conclusion, the present study supports the effectiveness of one-week high dose of β-alanine during a cycling training in World Tour cyclists to improve their uphill time-trial performance. In addition, it is important to highlight the potential role of β-alanine in improving recovery power. This aspect is particularly relevant in the context of a training camp, where fatigue levels can increase alongside training intensity. Trial registration: This study was registered in ClinicalTrials.gov: (identifier: NCT04427319)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pérez-Piñero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Co-twin studies are an elegant and powerful design that allows controlling for the effect of confounding variables, including genetic and a range of environmental factors. There are several approaches to carry out this design. One of the methods commonly used, when contrasting continuous variables, is to calculate difference scores between members of a twin pair on two associated variables, in order to analyse the covariation of such differences. However, information regarding whether and how the different ways of estimating within-pair difference scores may impact the results is scant. This study aimed to compare the results obtained by different methods of data transformation when performing a co-twin study and test how the magnitude of the association changes using each of those approaches. Data was simulated using a direction of causation model and by fixing the effect size of causal path to low, medium, and high values. Within-pair difference scores were calculated as relative scores for diverse within-pair ordering conditions or absolute scores. Pearson's correlations using relative difference scores vary across the established scenarios (how twins were ordered within pairs) and these discrepancies become larger as the within-twin correlation increases. Absolute difference scores tended to produce the lowest correlation in every condition. Our results show that both using absolute difference scores or ordering twins within pairs, may produce an artificial decrease in the magnitude of the studied association, obscuring the ability to detect patterns compatible with causation, which could lead to discrepancies across studies and erroneous conclusions., (© 2024. The Author(s).)

Introduction: With the increasing prevalence of atrial fibrillation (AF), it entails expanding oral anticoagulants (OACs) use, carrying a higher risk of associated hemorrhagic events, including intracranial hemorrhage (ICH). Despite advances in OACs development with a better safety profile and reversal agent for these anticoagulants, there is still no consensus on the optimal management of patients with OACs-associated ICH., Areas Covered: In this review, the authors have carried out an exhaustive search on the advances in recent years. The authors provide an update on the management of ICH in anticoagulated patients, as well as an update on the latest evidence on anticoagulation resumption, recent therapeutic strategies, and investigational drugs that could play a role in the future., Expert Opinion: Following an ICH event in an anticoagulated patient, a comprehensive clinical evaluation is imperative. Anticoagulation should be promptly withdrawn and reversed. Once the patient is stabilized, a reintroduction of anticoagulation should be considered, typically within a timeframe of 4-8 weeks, if feasible. If re-anticoagulation is not possible, alternative options such as Left Atrial Appendage Occlusion are available.

Introduction: Despite the increasing widespread adoption and experience in minimally invasive liver resections (MILR), open conversion occurs not uncommonly even with minor resections and as been reported to be associated with inferior outcomes. We aimed to identify risk factors for and outcomes of open conversion in patients undergoing minor hepatectomies. We also studied the impact of approach (laparoscopic or robotic) on outcomes., Methods: This is a post-hoc analysis of 20,019 patients who underwent RLR and LLR across 50 international centers between 2004-2020. Risk factors for and perioperative outcomes of open conversion were analysed. Multivariate and propensity score-matched analysis were performed to control for confounding factors., Results: Finally, 10,541 patients undergoing either laparoscopic (LLR; 89.1%) or robotic (RLR; 10.9%) minor liver resections (wedge resections, segmentectomies) were included. Multivariate analysis identified LLR, earlier period of MILR, malignant pathology, cirrhosis, portal hypertension, previous abdominal surgery, larger tumor size, and posterosuperior location as significant independent predictors of open conversion. The most common reason for conversion was technical issues (44.7%), followed by bleeding (27.2%), and oncological reasons (22.3%). After propensity score matching (PSM) of baseline characteristics, patients requiring open conversion had poorer outcomes compared with successful MILR cases as evidenced by longer operative times, more blood loss, higher requirement for perioperative transfusion, longer duration of hospitalization and higher morbidity, reoperation, and 90-day mortality rates., Conclusions: Multiple risk factors were associated with conversion of MILR even for minor hepatectomies, and open conversion was associated with significantly poorer perioperative outcomes., (© 2024. Society of Surgical Oncology.)

Background: Lung cancer risk prediction models might efficiently identify individuals who should be offered lung cancer screening. However, their performance has not been comprehensively evaluated in Europe. We aimed to externally validate and evaluate the performance of several risk prediction models that predict lung cancer incidence or mortality in prospective European cohorts., Methods: We analysed 240 137 participants aged 45-80 years with a current or former smoking history from nine European countries in four prospective cohorts from the pooled database of the Lung Cancer Cohort Consortium: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (Finland), the Nord-Trøndelag Health Study (Norway), CONSTANCES (France), and the European Prospective Investigation into Cancer and Nutrition (Denmark, Germany, Italy, Spain, Sweden, the Netherlands, and Norway). We evaluated ten lung cancer risk models, which comprised the Bach, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 model (PLCO m2012 ), the Lung Cancer Risk Assessment Tool (LCRAT), the Lung Cancer Death Risk Assessment Tool (LCDRAT), the Nord-Trøndelag Health Study (HUNT), the Optimized Early Warning Model for Lung Cancer Risk (OWL), the University College London-Death (UCLD), the University College London-Incidence (UCLI), the Liverpool Lung Project version 2 (LLP version 2), and the Liverpool Lung Project version 3 (LLP version 3) models. We quantified model calibration as the ratio of expected to observed cases or deaths and discrimination using the area under the receiver operating characteristic curve (AUC). For each model, we also identified risk thresholds that would screen the same number of individuals as each of the US Preventive Services Task Force 2021 (USPSTF-2021), the US Preventive Services Task Force 2013 (USPSTF-2013), and the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) criteria., Findings: Among the participants, 1734 lung cancer cases and 1072 lung cancer deaths occurred within five years of enrolment. Most models had reasonable calibration in most countries, although the LLP version 2 overpredicted risk by more than 50% in eight countries (expected to observed ≥1·50). The PLCO m2012 , LCDRAT, LCRAT, Bach, HUNT, OWL, UCLD, and UCLI models showed similar discrimination in most countries, with AUCs ranging from 0·68 (95% CI 0·59-0·77) to 0·83 (0·78-0·89), whereas the LLP version 2 and LLP version 3 showed lower discrimination, with AUCs ranging from 0·64 (95% CI 0·57-0·72) to 0·78 (0·74-0·83). When pooling data from all countries (but excluding the HUNT cohort), 33·9% (73 313 of 216 387) of individuals were eligible by USPSTF-2021 criteria, which included 74·8% (1185) of lung cancers and 76·3% (730) of lung cancer deaths occurring over 5 years. Fewer individuals were selected by USPSTF-2013 and NELSON criteria. After applying thresholds to select a population of equal size to USPSTF-2021, the PLCO m2012 , LCDRAT, LCRAT, Bach, HUNT, OWL, UCLD, and UCLI, models identified 77·6%-79·1% of future cases, although they selected slightly older individuals compared with USPSTF-2021 criteria. Results were similar for USPSTF-2013 and NELSON., Interpretation: Several lung cancer risk prediction models showed good performance in European countries and might improve the efficiency of lung cancer screening if used in place of categorical eligibility criteria., Funding: US National Cancer Institute, l'Institut National du Cancer, Cancer Research UK., Competing Interests: Declaration of interests We declare no competing interests. Where authors are identified as personnel of the International Agency for Research on Cancer or WHO, the authors alone are responsible for the views expressed in this Article and they do not necessarily represent the decisions, policy, or views of those organisations., (This is an Open Access article published under the CC BY NC ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

A priority to facilitate the application of lipofection to generate genetically modified porcine embryos and animals will be the use of zona pellucida (ZP)-intact oocytes and zygotes. Recently, our group produced genetically modified embryos by lipofection of ZP-intact oocytes during in vitro fertilization (IVF). This study investigates the effect of two commercial lipofection reagents, Lipofectamine 3000 and Lipofectamine CRISPRMAX, on embryo development and mutation efficiency in ZP-intact porcine oocytes. We compared these reagents with the electroporation method and a control group using two sgRNAs targeting the CAPN3 and CD163 genes. The detrimental effects on cleavage rates were observed in both lipofection treatments compared to the control and electroporated groups. However, blastocyst rates were higher in the Lipofectamine 3000 group than in the electroporated group for both genes. Mutation parameters varied by target gene, with Lipofectamine 3000 achieving higher mutation rates for CD163, while all groups were similar for the CAPN3 gene. Overall efficiency was similar for both lipofectamines, confirming their feasibility for use. In addition, we evaluated the effect of coincubation time (4, 8, and 24 h) on IVF outcomes, embryo development, and mutation parameters. Results indicated that an 8-h coincubation period optimized fertilization and mutation efficiency without significant toxic effects. This study demonstrates that lipofection with either Lipofectamine 3000 or CRISPRMAX during IVF is an effective method for generating genetically modified porcine embryos without the need for specialized equipment or trained personnel, with efficiencies similar to or greater than electroporation. This study also highlights the importance of optimizing reagent selection and coincubation times. There is no difference between Lipofectamine 3000 and CRISPRMAXTM in terms of embryo development and mutation efficiency, and under our experimental conditions, the optimal coincubation time with lipofectamine is 8 h., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, N ε -[carboxy-methyl]lysine (CML), N ε -[carboxy-ethyl]lysine (CEL) and N δ -[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (P interaction  = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HR Q5vs.Q1  = 1.67, 95% CI: 1.21-2.30, P trend  = .02) or any cause (HR Q5vs.Q1  = 1.38, 95% CI: 1.05-1.83, P trend  = .09). These associations tended to be stronger among cases with diabetes (P interaction  = .03) and pre-diabetes (P interaction  <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes., (© 2024 UICC.)

Background and Aims: Somatic mutations in the TET2 gene that lead to clonal haematopoiesis (CH) are associated with accelerated atherosclerosis development in mice and a higher risk of atherosclerotic disease in humans. Mechanistically, these observations have been linked to exacerbated vascular inflammation. This study aimed to evaluate whether colchicine, a widely available and inexpensive anti-inflammatory drug, prevents the accelerated atherosclerosis associated with TET2-mutant CH., Methods: In mice, TET2-mutant CH was modelled using bone marrow transplantations in atherosclerosis-prone Ldlr-/- mice. Haematopoietic chimeras carrying initially 10% Tet2-/- haematopoietic cells were fed a high-cholesterol diet and treated with colchicine or placebo. In humans, whole-exome sequencing data and clinical data from 37 181 participants in the Mass General Brigham Biobank and 437 236 participants in the UK Biobank were analysed to examine the potential modifying effect of colchicine prescription on the relationship between CH and myocardial infarction., Results: Colchicine prevented accelerated atherosclerosis development in the mouse model of TET2-mutant CH, in parallel with suppression of interleukin-1β overproduction in conditions of TET2 loss of function. In humans, patients who were prescribed colchicine had attenuated associations between TET2 mutations and myocardial infarction. This interaction was not observed for other mutated genes., Conclusions: These results highlight the potential value of colchicine to mitigate the higher cardiovascular risk of carriers of somatic TET2 mutations in blood cells. These observations set the basis for the development of clinical trials that evaluate the efficacy of precision medicine approaches tailored to the effects of specific mutations linked to CH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)