The TEOGIC study project: a comprehensive characterization of early onset gastrointestinal cancer in the Northern area of Spain.

BACKGROUND: Gastrointestinal cancers represent one of the most prevalent diseases worldwide. Strikingly, the incidence of Early Onset Gastrointestinal Cancer (EOGIC) has been rising during the last decades and changes in lifestyle and environmental exposure seem to play a role. EOGIC has been defined as a different entity compared to on-average gastrointestinal cancer, with distinct clinical and molecular characteristics. Inherent to the particularities of younger age, there is an unmet need for a tailored approach for the management of these patients. The TEOGIC proposes a comprehensive study to characterize EOGIC patients in the northern of Spain. METHODS: Patients with histologically confirmed new diagnosis of colorectal, gastroesophageal and pancreatic adenocarcinoma will be considered for two cohorts: EOGIC (≤ 50 years old) and non-EOGIC (60-75 years old), with a ratio of 1:2. Two hundred and forty patients will be recruited in 4 Public Hospitals from northern Spain. After receiving unified informed consent, demographic and clinical data of the patients will be collected in a REDCap database. Lifestyle related data will be obtained in questionnaires assessing diet, physical activity and the general quality of life of the patients before diagnosis. Biological samples prior to any onco-specific treatment will be obtained for the analyses of circulating inflammatory proteins, gut microbiota, and the proteome of the tumor microenvironment. Histologic characteristics and routine biomarkers will be also collected. Thereafter, data will be integrated and analyzed to assess tumor specific, pan-tumor and sex-associated differential characteristics of EOGIC. DISCUSSION: The underlying risk factors and differential characteristics of EOGIC remain poorly studied, particularly in our geographical area. Although limited by the exploratory nature and the small sample size estimated to be recruited, TEOGIC represents the first attempt to comprehensively characterize these young patients, and thus attend to their special needs. Findings derived from this study could contribute to raise awareness and preventive behaviors in the population. In parallel, molecular studies could lead to the identification of potential novel non-invasive biomarkers and therapeutic targets that would help in the development of the tailored clinical management of these patients, focusing on screening programs for early diagnosis and precision medicine.

Mancha3D Code: Multipurpose Advanced Nonideal MHD Code for High-Resolution Simulations in Astrophysics.

The Mancha3D code is a versatile tool for numerical simulations of magnetohydrodynamic (MHD) processes in solar/stellar atmospheres. The code includes nonideal physics derived from plasma partial ionization, a realistic equation of state and radiative transfer, which allows performing high-quality realistic simulations of magnetoconvection, as well as idealized simulations of particular processes, such as wave propagation, instabilities or energetic events. The paper summarizes the equations and methods used in the Mancha3D (Multifluid (-purpose -physics -dimensional) Advanced Non-ideal MHD Code for High resolution simulations in Astrophysics 3D) code. It also describes its numerical stability and parallel performance and efficiency. The code is based on a finite difference discretization and a memory-saving Runge-Kutta (RK) scheme. It handles nonideal effects through super-time-stepping and Hall diffusion schemes, and takes into account thermal conduction by solving an additional hyperbolic equation for the heat flux. The code is easily configurable to perform different kinds of simulations. Several examples of the code usage are given. It is demonstrated that splitting variables into equilibrium and perturbation parts is essential for simulations of wave propagation in a static background. A perfectly matched layer (PML) boundary condition built into the code greatly facilitates a nonreflective open boundary implementation. Spatial filtering is an important numerical remedy to eliminate grid-size perturbations enhancing the code stability. Parallel performance analysis reveals that the code is strongly memory bound, which is a natural consequence of the numerical techniques used, such as split variables and PML boundary conditions. Both strong and weak scalings show adequate performance up to several thousands of processors (CPUs).

Validation of machine-learning model for first-trimester prediction of pre-eclampsia using cohort from PREVAL study.

OBJECTIVE: Effective first-trimester screening for pre-eclampsia (PE) can be achieved using a competing-risks model that combines risk factors from the maternal history with multiples of the median (MoM) values of biomarkers. A new model using artificial intelligence through machine-learning methods has been shown to achieve similar screening performance without the need for conversion of raw data of biomarkers into MoM. This study aimed to investigate whether this model can be used across populations without specific adaptations. METHODS: Previously, a machine-learning model derived with the use of a fully connected neural network for first-trimester prediction of early (< 34 weeks), preterm (< 37 weeks) and all PE was developed and tested in a cohort of pregnant women in the UK. The model was based on maternal risk factors and mean arterial blood pressure (MAP), uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A). In this study, the model was applied to a dataset of 10 110 singleton pregnancies examined in Spain who participated in the first-trimester PE validation (PREVAL) study, in which first-trimester screening for PE was carried out using the Fetal Medicine Foundation (FMF) competing-risks model. The performance of screening was assessed by examining the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% screen-positive rate (SPR). These indices were compared with those derived from the application of the FMF competing-risks model. The performance of screening was poor if no adjustment was made for the analyzer used to measure PlGF, which was different in the UK and Spain. Therefore, adjustment for the analyzer used was performed using simple linear regression. RESULTS: The DRs at 10% SPR for early, preterm and all PE with the machine-learning model were 84.4% (95% CI, 67.2-94.7%), 77.8% (95% CI, 66.4-86.7%) and 55.7% (95% CI, 49.0-62.2%), respectively, with the corresponding AUCs of 0.920 (95% CI, 0.864-0.975), 0.913 (95% CI, 0.882-0.944) and 0.846 (95% CI, 0.820-0.872). This performance was achieved with the use of three of the biomarkers (MAP, UtA-PI and PlGF); inclusion of PAPP-A did not provide significant improvement in DR. The machine-learning model had similar performance to that achieved by the FMF competing-risks model (DR at 10% SPR, 82.7% (95% CI, 69.6-95.8%) for early PE, 72.7% (95% CI, 62.9-82.6%) for preterm PE and 55.1% (95% CI, 48.8-61.4%) for all PE) without requiring specific adaptations to the population. CONCLUSIONS: A machine-learning model for first-trimester prediction of PE based on a neural network provides effective screening for PE that can be applied in different populations. However, before doing so, it is essential to make adjustments for the analyzer used for biochemical testing. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Comparison of different methods of first-trimester screening for preterm pre-eclampsia: cohort study.

OBJECTIVE: To compare the predictive performance of three different mathematical models for first-trimester screening of pre-eclampsia (PE), which combine maternal risk factors with mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF), and two risk-scoring systems. METHODS: This was a prospective cohort study performed in eight fetal medicine units in five different regions of Spain between September 2017 and December 2019. All pregnant women with singleton pregnancy and a non-malformed live fetus attending their routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation were invited to participate in the study. Maternal characteristics and medical history were recorded and measurements of MAP, UtA-PI, serum PlGF and pregnancy-associated plasma protein-A (PAPP-A) were converted into multiples of the median (MoM). Risks for term PE, preterm PE (< 37 weeks' gestation) and early PE (< 34 weeks' gestation) were calculated according to the FMF competing-risks model, the Crovetto et al. logistic regression model and the Serra et al. Gaussian model. PE classification was also performed based on the recommendations of the National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG). We estimated detection rates (DR) with their 95% CIs at a fixed 10% screen-positive rate (SPR), as well as the area under the receiver-operating-characteristics curve (AUC) for preterm PE, early PE and all PE for the three mathematical models. For the scoring systems, we calculated DR and SPR. Risk calibration was also assessed. RESULTS: The study population comprised 10 110 singleton pregnancies, including 32 (0.3%) that developed early PE, 72 (0.7%) that developed preterm PE and 230 (2.3%) with any PE. At a fixed 10% SPR, the FMF, Crovetto et al. and Serra et al. models detected 82.7% (95% CI, 69.6-95.8%), 73.8% (95% CI, 58.7-88.9%) and 79.8% (95% CI, 66.1-93.5%) of early PE; 72.7% (95% CI, 62.9-82.6%), 69.2% (95% CI, 58.8-79.6%) and 74.1% (95% CI, 64.2-83.9%) of preterm PE; and 55.1% (95% CI, 48.8-61.4%), 47.1% (95% CI, 40.6-53.5%) and 53.9% (95% CI, 47.4-60.4%) of all PE, respectively. The best correlation between predicted and observed cases was achieved by the FMF model, with an AUC of 0.911 (95% CI, 0.879-0.943), a slope of 0.983 (95% CI, 0.846-1.120) and an intercept of 0.154 (95% CI, -0.091 to 0.397). The NICE criteria identified 46.7% (95% CI, 35.3-58.0%) of preterm PE at 11% SPR and ACOG criteria identified 65.9% (95% CI, 55.4-76.4%) of preterm PE at 33.8% SPR. CONCLUSIONS: The best performance of screening for preterm PE is achieved by mathematical models that combine maternal factors with MAP, UtA-PI and PlGF, as compared to risk-scoring systems such as those of NICE and ACOG. While all three algorithms show similar results in terms of overall prediction, the FMF model showed the best performance at an individual level. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

The influence of thermal pressure gradients and ionization (im)balance on the ambipolar diffusion and charge-neutral drifts.

Solar partially ionized plasma is frequently modelled using single-fluid (1F) or two-fluid (2F) approaches. In the 1F case, charge-neutral interactions are often described through ambipolar diffusion, while the 2F model fully considers charge-neutral drifts. Here, we expand the definition of the ambipolar diffusion coefficient to include inelastic collisions (ion/rec) in two cases: a VAL3C one-dimensional model and a 2F simulation of the Rayleigh-Taylor instability (RTI) in a solar prominence thread based on [Lukin et al. 2024 Phil. Trans. R. Soc. A 382, 20230417. (doi:10.1098/rsta.2023.0417)]. On one side, we evaluate the relative importance of the inelastic contribution, compared to elastic and charge-exchange collisions. On the other side, we compare the contributions of ion/rec, thermal pressure, viscosity and magnetic forces to the charge-neutral drift velocity of the turbulent flow of the RTI. Our analysis reveals that the contribution of inelastic collisions to the ambipolar diffusion coefficient is negligible across the chromosphere, allowing the classical definition of this coefficient to be safely used in 1F modelling. However, in the transition region, the contribution of inelastic collisions can become as significant as that of elastic collisions. Furthermore, we ascertain that the thermal pressure force predominantly influences the charge-neutral drifts in the RTI model, surpassing the impact of the magnetic force. This article is part of the theme issue 'Partially ionized plasma of the solar atmosphere: recent advances and future pathways'.

Physicochemical Characterization of a Biomimetic, Elastin-Inspired Polypeptide with Enhanced Thermoresponsive Properties and Improved Cell Adhesion.

Genetic engineering allows fine-tuning and controlling protein properties, thus exploiting the new derivatives to obtain novel materials and systems with improved capacity to actively interact with biological systems. The elastin-like polypeptides are tunable recombinant biopolymers that have proven to be ideal candidates for realizing bioactive interfaces that can interact with biological systems. They are characterized by a thermoresponsive behavior that is strictly related to their peculiar amino acid sequence. We describe here the rational design of a new biopolymer inspired by elastin and the comparison of its physicochemical properties with those of another already characterized member of the same protein class. To assess the cytocompatibility, the behavior of cells of different origins toward these components was evaluated. Our study shows that the biomimetic strategy adopted to design new elastin-based recombinant polypeptides represents a versatile and valuable tool for the development of protein-based materials with improved properties and advanced functionality.

Photo-induced crosslinking uncovers an antiparallel strand orientation in heterodimeric (EIAALEK)3/(KIAALKE)3 and (EIAALEK)3/(RIAALRE)3 coiled-coil systems.

We describe for the first time the co-existence of the parallel and antiparallel conformation of the heterodimeric E3/K3 and E3/R3 coiled-coil systems in solution. The introduction of a furanylated amino acid in the (EIAALEK)3 sequence allowed, upon photo-induced covalent crosslinking, freezing of the respective coiled-coil complexes present in solution. The occurrence of both parallel and antiparallel conformations in solution was supported by computational simulations and further confirmed by fluorescence experiments based on pyrene-pyrene stacking.

Performance of first-trimester combined screening for preterm pre-eclampsia: findings from cohort of 10 110 pregnancies in Spain.

OBJECTIVE: To evaluate the diagnostic accuracy of the Fetal Medicine Foundation (FMF) competing-risks model, incorporating maternal characteristics, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and placental growth factor (PlGF) (the 'triple test'), for the prediction at 11-13 weeks' gestation of preterm pre-eclampsia (PE) in a Spanish population. METHODS: This was a prospective cohort study performed in eight fetal medicine units in five different regions of Spain between September 2017 and December 2019. All pregnant women with a singleton pregnancy and a non-malformed live fetus attending a routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation were invited to participate. Maternal demographic characteristics and medical history were recorded and MAP, UtA-PI, serum PlGF and pregnancy-associated plasma protein-A (PAPP-A) were measured following standardized protocols. Treatment with aspirin during pregnancy was also recorded. Raw values of biomarkers were converted into multiples of the median (MoM), and audits were performed periodically to provide regular feedback to operators and laboratories. Patient-specific risks for term and preterm PE were calculated according to the FMF competing-risks model, blinded to pregnancy outcome. The performance of screening for PE, taking into account aspirin use, was assessed by calculating the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% fixed screen-positive rate (SPR). Risk calibration of the model was assessed. RESULTS: The study population comprised 10 110 singleton pregnancies, including 72 (0.7%) that developed preterm PE. In the preterm PE group, compared to those without PE, median MAP MoM and UtA-PI MoM were significantly higher, and median serum PlGF MoM and PAPP-A MoM were significantly lower. In women with PE, the deviation from normal in all biomarkers was inversely related to gestational age at delivery. Screening for preterm PE by a combination of maternal characteristics and medical history with MAP, UtA-PI and PlGF had a DR, at 10% SPR, of 72.7% (95% CI, 62.9-82.6%). An alternative strategy of replacing PlGF with PAPP-A in the triple test was associated with poorer screening performance for preterm PE, giving a DR of 66.5% (95% CI, 55.8-77.2%). The calibration plot showed good agreement between predicted risk and observed incidence of preterm PE, with a slope of 0.983 (95% CI, 0.846-1.120) and an intercept of 0.154 (95% CI, -0.091 to 0.397). CONCLUSIONS: The FMF model is effective in predicting preterm PE in the Spanish population at 11-13 weeks' gestation. This method of screening is feasible to implement in routine clinical practice, but it should be accompanied by a robust audit and monitoring system, in order to maintain high-quality screening. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

A randomized controlled trial investigating the effect of transport duration and age at transport on surplus dairy calves: Part II. Impact on hematological variables.

Surplus dairy calves often arrive at veal and dairy-beef rearing facilities with health and blood metabolite level abnormalities, which can affect their welfare and performance, predisposing them to future health challenges. The objective of this randomized controlled trial was to investigate the effects of transport duration and age at the time of transport on blood parameters in surplus dairy calves following 6, 12, or 16 h of continuous road transportation. All surplus calves from 5 commercial dairy farms in Ontario were enrolled and examined daily before transport (n = 175). On the day of transportation, calves were weighed, blood sampled, and randomly assigned to 6, 12, or 16 h of transportation. Blood samples were then collected immediately after transportation, as well as 24, 48, and 72 h thereafter. Serum was analyzed at a provincial diagnostic laboratory for nonesterified fatty acids (NEFA), ß-hydroxybutyric acid (BHBA), creatine kinase (CK), cholesterol, and haptoglobin. In addition, blood gas and electrolyte values were also assessed at the time of sample collection. Mixed models with repeated measures were used to assess the effects of transport duration, breed, sex, transfer of passive immunity status, weight before transportation, and age at transportation on blood parameters. Immediately following transportation, NEFA and BHBA were greater for calves transported for 12 h (Δ = 0.22 mmol/L NEFA, 95% CI = 0.15 to 0.30; Δ = 0.04 mmol/L BHBA, 95% CI = 0.02 to 0.06) and 16 h (Δ = 0.35 mmol/L NEFA, 95% CI = 0.27 to 0.42; Δ = 0.10 mmol/L BHBA, 95% CI = 0.08 to 0.11) compared with calves transported for 6 h. Glucose was lower immediately following transportation in calves transported for 16 h compared with 6 h (Δ = -15.54 mg/dL, 95% CI = -21.54 to -9.54). In addition, pH and HCO3- were lower in calves transported for 12 (Δ = -0.09 pH, 95% CI = -0.13 to -0.05; Δ = -1.59 mmol/L HCO3-, 95% CI = -2.61 to -0.56) and 16 h (Δ = -0.07 pH, 95% CI = -0.12 to -0.03; Δ = -1.95 mmol/L HCO3-, 95% CI = -2.95 to -0.95) compared with calves transported for 6 h. Calves transported between 15 and 19 d of age had a higher concentration of cholesterol and CK (Δ = 0.27 mmol/L cholesterol; 37.18 U/L CK) compared with 2- to 6-d-old calves, and calves 12 to 14 d old had greater reduction in HCO3- (Δ = -0.92 mmol/L) compared with 2- to 6-d-old calves. These findings show that transporting calves for long distances results in lower glucose concentration and suboptimal energy status, and that this effect varies based on the calf's age.

Aqueous Extracts from Hemp Seeds as a New Weapon against Staphylococcus epidermidis Biofilms.

This study investigated the antibiofilm activity of water-soluble extracts obtained under different pH conditions from Cannabis sativa seeds and from previously defatted seeds. The chemical composition of the extracts, determined through GC-MS and NMR, revealed complex mixtures of fatty acids, monosaccharides, amino acids and glycerol in ratios depending on extraction pH. In particular, the extract obtained at pH 7 from defatted seeds (Ex7d) contained a larger variety of sugars compared to the others. Saturated and unsaturated fatty acids were found in all of the analysed extracts, but linoleic acid (C18:2) was detected only in the extracts obtained at pH 7 and pH 10. The extracts did not show cytotoxicity to HaCaT cells and significantly inhibited the formation of Staphylococcus epidermidis biofilms. The exception was the extract obtained at pH 10, which appeared to be less active. Ex7d showed the highest antibiofilm activity, i.e., around 90%. Ex7d was further fractionated by HPLC, and the antibiofilm activity of all fractions was evaluated. The 2D-NMR analysis highlighted that the most active fraction was largely composed of glycerolipids. This evidence suggested that these molecules are probably responsible for the observed antibiofilm effect but does not exclude a possible synergistic contribution by the other components.

Probing Flat Band Physics in Spin Ice Systems via Polarized Neutron Scattering.

In this Letter, we illustrate how polarized neutron scattering can be used to isolate the spin-spin correlations of modes forming flat bands in a frustrated magnetic system hosting a classical spin liquid phase. In particular, we explain why the nearest-neighbor spin ice model, whose interaction matrix has two flat bands, produces a dispersionless (i.e., "flat") response in the non-spin-flip (NSF) polarized neutron scattering channel and demonstrate that NSF scattering is a highly sensitive probe of correlations induced by weak perturbations that lift the flat band degeneracy. We use this to explain the experimentally measured dispersive (i.e., nonflat) NSF channel of the dipolar spin ice compound Ho_{2}Ti_{2}O_{7}.

Effect of routine first-trimester combined screening for pre-eclampsia on small-for-gestational-age birth: secondary interrupted time series analysis.

OBJECTIVE: To evaluate the impact of a first-trimester combined screening program for pre-eclampsia, based on the Fetal Medicine Foundation (FMF) algorithm, on the rate of small-for-gestational age (SGA) at birth and adverse pregnancy outcome. METHODS: This was a retrospective cohort study of data obtained from a London tertiary hospital between January 2017 and March 2019. The data were derived from a secondary analysis of the cohort evaluated in a clinical-effectiveness study on the implementation of a first-trimester screening program for pre-eclampsia. The cohort included 7720 women screened according to the UK National Institute for Health and Care Excellence (NICE) risk-based approach and 4841 women screened by the FMF multimodal approach, which combines maternal risk factors, blood pressure, pregnancy-associated plasma protein-A and uterine artery Doppler indices. The care package for the FMF-screened group included 150-mg aspirin prophylaxis, ultrasound scans at 28 and 36 weeks' gestation and scheduled delivery at 40 weeks. Outcome measures included the rates of SGA neonates at birth, admission to the neonatal unit, intrauterine demise, neonatal death and hypoxic-ischemic encephalopathy assessed by interrupted time series analysis (ITSA). RESULTS: There was no significant difference in the rates of intrauterine demise, neonatal death and hypoxic-ischemic encephalopathy between the FMF-screened and NICE-screened cohorts. ITSA showed a significant reduction in the rate of term SGA birth < 10th percentile at 21 months following implementation of the FMF screening program, with a relative effect reduction of 45.1% (P = 0.004). However, there was no significant relative effect reduction in term SGA birth < 5th or < 3rd percentile. CONCLUSIONS: First-trimester combined screening for pre-eclampsia based on the FMF algorithm accompanied by a care package including serial ultrasound scans for growth evaluation and elective birth from 40 weeks' gestation resulted in a significant 45% relative effect reduction in term SGA birth < 10th percentile but did not affect term SGA birth < 5th or < 3rd percentile. Further screening strategies to detect and improve the outcome of cases with SGA birth < 5th percentile need to be considered. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Implementation of routine first trimester combined screening for pre-eclampsia: a clinical effectiveness study.

OBJECTIVE: Evaluate clinical effectiveness of the first trimester combined (FMF) pre-eclampsia screening programme when implemented in a public healthcare setting. DESIGN: Retrospective cohort study. SETTING: London tertiary hospital from January 2017 to March 2019. METHODS: 7720 women screened for pre-eclampsia according to National Institute for Health and Care Excellence (NICE) risk-based guidance and 4841 by the Fetal Medical Foundation (FMF) algorithm which combined maternal risk factors, blood pressure, PAPP-A and uterine artery Doppler indices in the first trimester. High risk was defined by standard NICE criteria in the pre-intervention cohort (prescribed 75 mg aspirin) or a risk of ≥1:50 for preterm pre-eclampsia from the FMF algorithm in the post-intervention cohort (prescribed 150 mg aspirin). MAIN OUTCOME MEASURES: Screening effectiveness, rates of pre-eclampsia. RESULTS: The FMF screening programme resulted in a significant reduction in the screen-positive rate (16.1 versus 8.2%, odds ratio [OR] 0.50, 95% confidence interval [CI] 0.41-0.53) with a concurrent increase in targeted aspirin use in women classified as high risk for pre-eclampsia (28.9 versus 99.0%, OR 241.6, 95% CI 89.6-652.0). Screening indices were uniformly improved for the FMF algorithm with receiver operating characteristic (ROC) analysis demonstrating excellent discrimination for preterm pre-eclampsia (area under the curve [AUC] = 0.846, 95% CI 0.778-0.915, P value <.001). Interrupted time series analysis showed that the FMF screening programme resulted in a significant 21-month relative effect reduction of 80% (P = .025) and 89% (P = .017), for preterm and early pre-eclampsia, respectively. CONCLUSIONS: First trimester combined screening for pre-eclampsia is both feasible and effective in a public healthcare setting. Such an approach results in a two-fold de-escalation of risk, doubling of pre-eclampsia detection, near total physician compliance of aspirin use and a significant reduction in the prevalence of preterm pre-eclampsia. TWEETABLE ABSTRACT: Implementation of 1st trimester combined pre-eclampsia screening effectively reduces prevalence of the disorder.

Pattern forming systems coupling linear bulk diffusion to dynamically active membranes or cells.

Some analytical and numerical results are presented for pattern formation properties associated with novel types of reaction-diffusion (RD) systems that involve the coupling of bulk diffusion in the interior of a multi-dimensional spatial domain to nonlinear processes that occur either on the domain boundary or within localized compartments that are confined within the domain. The class of bulk-membrane system considered herein is derived from an asymptotic analysis in the limit of small thickness of a thin domain that surrounds the bulk medium. When the bulk domain is a two-dimensional disk, a weakly nonlinear analysis is used to characterize Turing and Hopf bifurcations that can arise from the linearization around a radially symmetric, but spatially non-uniform, steady-state of the bulk-membrane system. In a singularly perturbed limit, the existence and linear stability of localized membrane-bound spike patterns is analysed for a Gierer-Meinhardt activator-inhibitor model that includes bulk coupling. Finally, the emergence of collective intracellular oscillations is studied for a class of PDE-ODE bulk-cell model in a bounded two-dimensional domain that contains spatially localized, but dynamically active, circular cells that are coupled through a linear bulk diffusion field. Applications of such coupled bulk-membrane or bulk-cell systems to some biological systems are outlined, and some open problems in this area are discussed. This article is part of the theme issue 'Recent progress and open frontiers in Turing's theory of morphogenesis'.

Laparoscopic versus open extended radical left pancreatectomy for pancreatic ductal adenocarcinoma: an international propensity-score matched study.

BACKGROUND: A radical left pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC) may require extended, multivisceral resections. The role of a laparoscopic approach in extended radical left pancreatectomy (ERLP) is unclear since comparative studies are lacking. The aim of this study was to compare outcomes after laparoscopic vs open ERLP in patients with PDAC. METHODS: An international multicenter propensity-score matched study including patients who underwent either laparoscopic or open ERLP (L-ERLP; O-ERLP) for PDAC was performed (2007-2015). The ISGPS definition for extended resection was used. Primary outcomes were overall survival, margin negative rate (R0), and lymph node retrieval. RESULTS: Between 2007 and 2015, 320 patients underwent ERLP in 34 centers from 12 countries (65 L-ERLP vs. 255 O-ERLP). After propensity-score matching, 44 L-ERLP could be matched to 44 O-ERLP. In the matched cohort, the conversion rate in L-ERLP group was 35%. The L-ERLP R0 resection rate (matched cohort) was comparable to O-ERLP (67% vs 48%; P = 0.063) but the lymph node yield was lower for L-ERLP than O-ERLP (median 11 vs 19, P = 0.023). L-ERLP was associated with less delayed gastric emptying (0% vs 16%, P = 0.006) and shorter hospital stay (median 9 vs 13 days, P = 0.005), as compared to O-ERLP. Outcomes were comparable for additional organ resections, vascular resections (besides splenic vessels), Clavien-Dindo grade ≥ III complications, or 90-day mortality (2% vs 2%, P = 0.973). The median overall survival was comparable between both groups (19 vs 20 months, P = 0.571). Conversion did not worsen outcomes in L-ERLP. CONCLUSION: The laparoscopic approach may be used safely in selected patients requiring ERLP for PDAC, since morbidity, mortality, and overall survival seem comparable, as compared to O-ERLP. L-ERLP is associated with a high conversion rate and reduced lymph node yield but also with less delayed gastric emptying and a shorter hospital stay, as compared to O-ERLP.

Disability progression in multiple sclerosis is associated with plasma neuroactive steroid profile.

BACKGROUND: Neuroactive steroids (NASs) exert multiple biological effects on development and inflammation. The effects of NASs on disease progression in multiple sclerosis (MS) are uncertain, prompting analyses of NAS profiles during the transition from clinically isolated syndrome (CIS) to relapsing-remitting (RR) MS. METHODS: Subjects with CIS or RRMS and healthy controls (HCs) were recruited; demographic and clinical data as well as disability scores measured by the Expanded Disability Status Scale (EDSS) were recorded. Matched plasma NAS and amino acid (AA) concentrations were measured. RESULTS: HC (n = 17), CIS (n = 31), and RRMS (n = 33) groups showed similar ages and sex distribution although disability scores were higher in the RRMS group. The conversion rate of CIS to RRMS group was 51.6% (n = 16) during a mean follow-up period of 1.85 years. The RRMS group showed significantly higher mean allopregnanolone, aspartate, and taurine concentrations with lower epiallopregnanolone concentrations than CIS patients, and higher L-serine-O-phosphate and lower alanine, arginine, and glutamine concentrations than the HC group. Among CIS and RRMS groups, multivariate hierarchical regressions revealed that higher concentrations of plasma tetrahydrodeoxycorticosterone (THDOC) may predict disability worsening. CONCLUSIONS: RRMS and CIS patients exhibited differing concentrations of both NASs and AAs in plasma while both THDOC and pregnanolone might serve as biomarkers of disability worsening.

Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are increasingly used to treat advanced cancers. Despite data indicating exaggerated radiation toxicities in patients with autoimmune disease, the safety of thoracic radiotherapy in patients with prior ICI-associated immune-related adverse events (irAEs) is undefined. PATIENTS AND METHODS: Patients treated from 2014 to 2020 with ICIs were queried for receipt of corticosteroids and radiotherapy. Patients who received thoracic radiation after symptomatic irAEs were assessed for ≥grade 2 radiation pneumonitis (RP). Characteristics predictive of RP were assessed using logistic regression and response relationships were modeled. RESULTS: Among 496 assessed patients, 41 with irAE history subsequently treated with thoracic radiotherapy were analyzed. Most irAEs were grade 2 (n = 21) and 3 (n = 19). Median time from irAE onset to radiotherapy was 8.1 months. Most patients received stereotactic body radiation therapy (n = 20) or hypofractionated radiotherapy (n = 18). In total, 25 patients (61%) developed ≥grade 2 RP at a median of 4 months from radiotherapy and 11 months from onset of irAEs. Three months from RP onset, 16 of 24 (67%) assessable patients had persistent symptoms. Among patients with prior ICI pneumonitis (n = 6), five patients (83%) developed ≥grade 2 RP (grade 2, n = 3; grade ≥3, n = 2). The mean lung radiation dose (MLD) predicted for RP (odds ratio: 1.60, P = 0.00002). The relationship between MLD and RP was strong (area under the receiver-operating characteristic curve: 0.85) and showed an exaggerated dose-response. Among patients with an MLD >5 Gy (n = 26), 21 patients (81%) developed ≥grade 2 RP. CONCLUSION: This is the first study assessing the toxicity of radiotherapy among patients with prior irAEs from ICIs. Patients with prior irAEs were found to be at very high risk for clinically significant and persistent RP from thoracic radiotherapy. Careful consideration should be given to the possibility of an increased risk of RP, and close monitoring is recommended in these patients.

Analysis of the measurement uncertainty and its effects on noise mapping validations.

This paper addresses the use of noise measurements when noise mapping simulations are intended to be validated. For this, a discussion about the measurement uncertainty and how to include it in the process of validation is carried out. Then, the contribution provided by the geo-referencing error of a GPS and its impact in the uncertainty is assessed. This is achieved by means of environmental noise measurements, which are conducted based on the accuracy radius given by a standard GPS. Furthermore, an assessment of the approach is conducted by means of numerical simulations using the commercial package SoundPLAN. The results indicate that the uncertainty of noise measurements should be included as it restricts the validation threshold (usually assumed as ±3 dB). Furthermore, the error generated by the inaccuracy of the geo-referencing process increases the uncertainty of the measurements and, therefore, of the noise maps. Finally, a method to calculate a total uncertainty, which partially includes the contributions of the geo-referencing error is also proposed.

Self-sustaining treatment as a novel alternative for the stabilization of anaerobic digestate.

Self-sustaining smouldering combustion (SSS) is a technology based on the flameless oxidation of an organic substrate and limited by the rate at which oxygen is diffused to the surface of the substrate. This work aims to evaluate the SSS combustion as a treatment process for the stabilization of anaerobic digestate, determining the limits of operational conditions, (moisture content (MC), air flux) that allow for a self-sustaining process. Maximum possible MC was found at 82 wt% with Darcy air flux of 50 cm/s. The digestate destruction rate (kg/(h·m2), and the addition of sand as an inert solid, to enhance the oxygen diffusion, were also investigated. A sand/substrate mass ratio of 1 allowed for SSS at 85 wt% MC, but decreased the digestate destruction rate. The average composition of the emitted gases showed ca. 25% CO and 10% H2, whereas the analysis of the ashes showed almost complete digestate inertization.

Meta-analysis of randomized clinical trials of early versus delayed cholecystectomy for mild gallstone pancreatitis.

BACKGROUND: Gallstones account for 30-50 per cent of all presentations of acute pancreatitis. While the management of acute pancreatitis is usually supportive, definitive treatment of gallstone pancreatitis is cholecystectomy. Guidelines from the British Society of Gastroenterology suggest definitive treatment on index admission or within 2 weeks of discharge, whereas joint recommendations from the International Association of Pancreatology and the American Pancreatic Association recommend definitive treatment on index admission. Evidence suggests that uptake of these guidelines is low. METHODS: Embase, MEDLINE and Cochrane databases were searched for RCTs investigating early versus delayed cholecystectomy in patients with a confirmed diagnosis of mild gallstone pancreatitis. The pooled synthesis was undertaken using a random-effects meta-analysis of the primary outcome of recurrent biliary complications causing hospital readmission. Secondary outcomes included intraoperative and postoperative complications, and total length of hospital stay (LOS). All analyses were performed using RevMan5 software. RESULTS: Five RCTs were identified, which included 629 patients (318 in the early cholecystectomy (EC) group and 311 in the delayed cholecystectomy (DC) group). Recurrent biliary events that required readmission were reduced in patients undergoing EC compared with the number in patients having DC (odds ratio (OR) 0·17, 95 per cent c.i. 0·09 to 0·33). There was no difference in the rate of intraoperative (OR 0·58, 0·17 to 1·92) or postoperative (OR 0·78, 0·38 to 1·62) complications. CONCLUSION: EC following mild gallstone pancreatitis does not increase the risk of intraoperative or postoperative complications, but reduces the readmission rate for recurrent biliary complications.

ANTECEDENTES: Los cálculos biliares son el factor etiológico en el 30-50% de todas las formas de pancreatitis aguda. Si bien el tratamiento de la pancreatitis aguda suele ser de soporte, el tratamiento definitivo de la pancreatitis por litiasis biliar es la colecistectomía. La guía de la British Society of Gastroenterology sugiere efectuar el tratamiento definitivo en el mismo ingreso o dentro de las 2 semanas posteriores al alta, mientras que la International Association of Pancreatology y la American Pancreatic Association recomiendan de forma conjunta el tratamiento definitivo en el mismo ingreso. Los datos disponibles sugieren que el seguimiento de estas guías es bajo. MÉTODOS: Se realizó una búsqueda en las bases de datos EMBASE, MEDLINE y Cochrane. de los ensayos clínicos aleatorizados y controlados (randomized clinical trials, RCTs) que analizaron la colecistectomía precoz frente a la tardía en pacientes con una pancreatitis leve por litiasis biliar. Se efectuó un metaanálisis de efectos aleatorios en el que la variable principal era la recidiva de complicaciones biliares que motivasen el reingreso hospitalario. Como variables secundarias se analizaron las complicaciones intraoperatorias y postoperatorias. Así como la duración de la estancia hospitalaria (length of stay, LOS). Los análisis se realizaron utilizando el programa RevMan5. RESULTADOS: Se incluyeron 5 RCTs con 629 pacientes (grupo de colecistectomía temprana (early cholecystectomy, EC), n = 318; grupo de colecistectomía tardía (delayed cholecystectomy, DC); n = 311). La recidiva de la enfermedad biliar que requiriese reingreso hospitalario fue menor en los pacientes sometidos a EC en comparación con DC, (cociente de oportunidades, odds ratio, OR) 0,17 (i.c. del 95% 0,09-0,33). No hubo diferencias en la tasa de complicaciones intraoperatorias, OR 0,58 (i.c. del 95% 0,17-1,92) o postoperatorias, OR 0,78 (i.c. del 95% 0,38-1,62). CONCLUSIÓN: La EC después de una pancreatitis leve por litiasis biliar no aumenta el riesgo de complicaciones intraoperatorias o postoperatorias, pero reduce la tasa de reingreso por la recidiva de complicaciones biliares.