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Abstract Background Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy, most patients experience local and/or distant PDAC recurrence within 2 years. High-level evidence regarding the benefits of recurrence-focused surveillance after PDAC resection is missing, and the impact of early detection and treatment of recurrence on survival and quality of life is unknown. In most European countries, recurrence-focused follow-up after surgery for PDAC is currently lacking. Consequently, guidelines regarding postoperative surveillance are based on expert opinion and other low-level evidence. The recent emergence of more potent local and systemic treatment options for PDAC recurrence has increased interest in early diagnosis. To determine whether early detection and treatment of recurrence can lead to improved survival and quality of life, we designed an international randomized trial. Methods This randomized controlled trial is nested within an existing prospective cohort in pancreatic cancer centers in the Netherlands (Dutch Pancreatic Cancer Project; PACAP) and the United Kingdom (UK) (Pancreas Cancer: Observations of Practice and survival; PACOPS) according to the “Trials within Cohorts” (TwiCs) design. All PACAP/PACOPS participants with a macroscopically radical resection (R0-R1) of histologically confirmed PDAC, who provided informed consent for TwiCs and participation in quality of life questionnaires, are included. Participants randomized to the intervention arm are offered recurrence-focused surveillance, existing of clinical evaluation, serum cancer antigen (CA) 19–9 testing, and contrast-enhanced computed tomography (CT) of chest and abdomen every three months during the first 2 years after surgery. Participants in the control arm of the study will undergo non-standardized clinical follow-up, generally consisting of clinical follow-up with imaging and serum tumor marker testing only in case of onset of symptoms, according to local practice in the participating hospital. The primary endpoint is overall survival. Secondary endpoints include quality of life, patterns of recurrence, compliance to and costs of recurrence-focused follow-up, and the impact on recurrence-focused treatment. Discussion The RADAR-PANC trial will be the first randomized controlled trial to generate high level evidence for the current clinical equipoise regarding the value of recurrence-focused postoperative surveillance with serial tumor marker testing and routine imaging in patients after PDAC resection. The Trials within Cohort design allows us to study the acceptability of recurrence-focused surveillance among cohort participants and increases the generalizability of findings to the general population. While it is strongly encouraged to offer all trial participants treatment at time of recurrence diagnosis, type and timing of treatment will be determined through shared decision-making. This might reduce the potential survival benefits of recurrence-focused surveillance, although insights into the impact on patients’ quality of life will be obtained. Trial registration Clinicaltrials.gov, NCT04875325 . Registered on May 6, 2021.

In this article, we introduce spyro, a software stack to solve wave propagation in heterogeneous domains and perform full waveform inversion (FWI) employing the finite-element framework from Firedrake, a high-level Python package for the automated solution of partial differential equations using the finite-element method. The capability of the software is demonstrated by using a continuous Galerkin approach to perform FWI for seismic velocity model building, considering realistic geophysics examples. A time domain FWI approach that uses meshes composed of variably sized triangular elements to discretize the domain is detailed. To resolve both the forward and adjoint-state equations and to calculate a mesh-independent gradient associated with the FWI process, a fully explicit, variable higher-order (up to degree k=5 in 2D and k=3 in 3D) mass-lumping method is used. We show that, by adapting the triangular elements to the expected peak source frequency and properties of the wave field (e.g., local P-wave speed) and by leveraging higher-order basis functions, the number of degrees of freedom necessary to discretize the domain can be reduced. Results from wave simulations and FWIs in both 2D and 3D highlight our developments and demonstrate the benefits and challenges with using triangular meshes adapted to the material properties.

This paper details and tests numerical improvements to the ADvanced CIRCulation (ADCIRC) model, a widely used finite-element method shallow-water equation solver, to more accurately and efficiently model global storm tides with seamless local mesh refinement in storm landfall locations. The sensitivity to global unstructured mesh design was investigated using automatically generated triangular meshes with a global minimum element size (MinEle) that ranged from 1.5 to 6 km. We demonstrate that refining resolution based on topographic seabed gradients and employing a MinEle less than 3 km are important for the global accuracy of the simulated astronomical tide. Our recommended global mesh design (MinEle = 1.5 km) based on these results was locally refined down to two separate MinEle values (500 and 150 m) at the coastal landfall locations of two intense storms (Hurricane Katrina and Super Typhoon Haiyan) to demonstrate the model's capability for coastal storm tide simulations and to test the sensitivity to local mesh refinement. Simulated maximum storm tide elevations closely follow the lower envelope of observed high-water marks (HWMs) measured near the coast. In general, peak storm tide elevations along the open coast are decreased, and the timing of the peak occurs later with local coastal mesh refinement. However, this mesh refinement only has a significant positive impact on HWM errors in straits and inlets narrower than the MinEle and in bays and lakes separated from the ocean by these passages. Lastly, we demonstrate that the computational performance of the new numerical treatment is 1 to 2 orders of magnitude faster than studies using previous ADCIRC versions because gravity-wave-based stability constraints are removed, allowing for larger computational time steps.

Background Perioperative use of statins is reported to improve postoperative outcomes after cardiac and non‐cardiovascular surgery. The aim of this study was to investigate the influence of statins on postoperative outcomes including complications of grade IIIa and above, posthepatectomy liver failure (PHLF), and 90‐day mortality rates after liver resection. Methods Patients who underwent hepatectomy between 2013 and 2017 were reviewed to identify statin users and non‐users (controls). Propensity matching was conducted for age, BMI, type of surgery and preoperative co‐morbidities to compare subgroups. Univariable and multivariable analyses were performed for the following outcomes: 90‐day mortality, significant postoperative complications and PHLF. Results Of 890 patients who had liver resection during the study period, 162 (18·2 per cent) were taking perioperative statins. Propensity analysis selected two matched groups, each comprising 154 patients. Overall, 81 patients (9·1 per cent) developed complications of grade IIIa or above, and the 90‐day mortality rate was 3·4 per cent (30 patients), with no statistically significant difference when the groups were compared before and after matching. The rate of PHLF was significantly lower in patients on perioperative statins than in those not taking statins (10·5 versus 17·3 per cent respectively; P = 0·033); similar results were found after propensity matching (10·4 versus 20·8 per cent respectively; P = 0·026). Conclusion The rate of PHLF was significantly lower in patients taking perioperative statins, but there was no statistically significant difference in severe complications and mortality rates.

Background Early treatment is the only potential cure for periampullary cancer. The pathway to surgery is complex and involves multiple procedures across local and specialist hospitals. The aim of this study was to analyse variability within this pathway, and its impact on cost and outcomes. Methods Patients undergoing surgery for periampullary cancer (2011–2016) were identified retrospectively and their pathway to surgery was analysed. Patients who had early surgery (shortest quartile, Q1) were compared with those having late surgery (longest quartile, Q4). Results A total of 483 patients were included in the study, with 121 and 124 patients in Q1 and Q4 respectively. The median time from initial CT to surgery was 21 days for Q1 versus 112 days for Q4 (P

OceanMesh2D is a set of MATLAB functions with preprocessing and post-processing utilities to generate two-dimensional (2-D) unstructured meshes for coastal ocean circulation models. Mesh resolution is controlled according to a variety of feature-driven geometric and topo-bathymetric functions. Mesh generation is achieved through a force balance algorithm to locate vertices and a number of topological improvement strategies aimed at improving the worst-case triangle quality. The placement of vertices along the mesh boundary is adapted automatically according to the mesh size function, eliminating the need for contour simplification algorithms. The software expresses the mesh design and generation process via an objected-oriented framework that facilitates efficient workflows that are flexible and automatic. This paper illustrates the various capabilities of the software and demonstrates its utility in realistic applications by producing high-quality, multiscale, unstructured meshes.

Parenting quality is important in child development. In the presence of HIV poverty and life stress, parenting may be challenged and child development affected. This study examines cross-sectional associations of situational factors such as poverty, mental health, HIV status, living with a biological parent, and stigma with good parenting and child outcomes (n = 989; age = 4–13 years) within the Child Community Care study (South Africa and Malawi). A parenting measure was created from 10 variables comprising 6 child and 4 parent ratings. These were highly correlated. Total parenting score was generated on a 10-point continuous scale, with a good parenting cut-off then defined as ≥8 out of a possible 10. Five factors were associated with good parenting. Positively associated with good parenting were being the biological parent of the child, parental mental health and dwelling in households with multiple adults. Poverty and stigma were negatively associated with good parenting. Using multiple mediation analysis, a positive direct effect of good parenting was found on child self-esteem, child behaviour and educational risks with a partial mediation via child depression and trauma. These data highlight possible intervention points. Influences on parenting could be seen through being the biological parent, parental mental health, poverty and stigma. In these challenging environments, health, nutrition, mental health, education and treatment to keep parents alive are all clearly identified as potential pathways to ensure child well-being.

The influence of the solution environment on the solution crystallisation of the conformational polymorphic forms I and II of tolfenamic acid is assessed through integration of multi-scale (molecular, cluster and crystallographic) modelling with polymorphic screening using polythermal crystallisation as a function of solvent selection. Solid-state analysis reveals the contrasting crystal chemistry with the strongest synthon involving hydrogen bonding synthons and π–π van der Waals interactions for forms I and II, respectively. Analysis of the molecular conformational energies reveals molecular structures for forms I and II to be very close which is matched by their calculated lattice energies. Crystallisation as a function of both solute concentration and solution cooling rate reveals form II to be mostly more preferred than form I. The higher stability of the form II conformer together with its easier conformational adjustment during the formation of form II crystals, is consistent with its greater crystallisability compared to the more stable form I. Solute concentration analysis of the relative stabilities of the two forms as a function of their sizes reveals that smaller cluster sizes are required to stabilise the crystal structure for form I with respect to form II. Polymorphic screening as a function of solvent confirms the predicted poor crystallisability of form I whose crystallisation is preferred at higher initial solute concentrations and lower cooling rates in polar solvents but less so for the more apolar solvent toluene, the latter being consistent with π–π solute/solvent interactions promoting the formation of hydrogen bonded solute/solute synthons at the expense of π–π interactions. Modelling work correlates well with the observed crystallisation behaviour, highlighting the importance of understanding solvent selection and solution state structure at the molecular-scale level for directing polymorphic outcomes, as confirmed by the higher crystallisability of the metastable form II. [ABSTRACT FROM AUTHOR]

Para amino benzoic acid (PABA) has two well-characterised α- and β-polymorphic forms and, whilst both crystallise in the monoclinic space group P21/n, they have quite different crystal chemistry and crystallisability behaviour. Previous work has shown that the molecular conformation deformation energy in the crystalline state is higher for the β-form than for the α-form and that the lattice energy for the former converges more slowly than for the latter overall. This suggests that not only is there a higher barrier to crystallisation for the β-form but also that low solution supersaturations might be needed for it to preferentially nucleate. Additionally, solute cluster propensity and solute solvation energetic analysis highlight the importance of an aqueous solvation environment in inhibiting the α-form's strong OH⋯O carboxylic acid hydrogen bond (H-bond) dimer. Despite this, the detailed molecular-scale pathway from solvated molecules to 3D crystallographic structure still remains unclear, most notably regarding how the nucleation process is activated and how, as a result, this mediates the preferential formation of either of the two polymorphic forms. Molecular dynamics (MD) simulations coupled with FTIR studies and intermolecular synthon analysis address this issue through characterisation of the propensity of the incipient bulk synthons that are important in the crystallisation of the two polymorphic forms within the solution state. MD molecular trajectory analysis within crystallisation solutions reveals a greater propensity for OH⋯O synthons (both single H-bonds and homodimers) typical of the α-form and NH⋯O synthons found in both the α- and β-forms when compared to aqueous solution but much lower propensities for the β-form's "fingerprinting" OH⋯N and π–π stacking synthons. In contrast, data from the aqueous solution environment reveals a much greater propensity for the β-form's π–π interaction synthons. IR dilution studies in acetonitrile in the carbonyl region reveal the presence of two C＝O vibrational stretching bands, whose relative intensities vary as a function of solution dilution. These were assigned to the solvated PABA monomer and a COOH dimer of PABA. Similar data in ethanol shows a main C＝O stretching band with a shoulder peak suggesting a similar monomer vs. dimer speciation may exist in this solvent. The IR data is consistent with the organic solvent MD data, albeit the corresponding analysis for the aqueous solution was precluded due to the latter's strong OH vibrational mode which restricted validation in aqueous solutions. [ABSTRACT FROM AUTHOR]

Programming effects of maternal undernutrition on fetal metabolic and cardiovascular systems are well elucidated, yet a detailed characterization of maternal haemodynamics is not available. This study used comprehensive cardiovascular magnetic resonance (CMR) imaging to quantify maternal haemodynamics after 29 days (111-140 days) of late-gestation undernutrition (LGUN) in pregnant sheep. Control ewes received 100% of metabolizable energy requirements (MERs, n = 15), whereas LGUN ewes were globally nutrient restricted to 50% MER (n = 18), with a subset of fetuses undergoing continuous glucose infusion (LGUN + G, n = 6/18). Ewes underwent CMR (138-140 days' gestation), and placental tissue was collected the next day. Ewes in both LGUN groups had reduced body weight and mean blood glucose concentration across gestation. Ventricular dimensions were lower in both LGUN groups. Uterine artery blood flow (QUtA) was elevated in the LGUN group compared with controls, whereas peripheral blood flow was reduced and further diminished in LGUN + G. Maternal weight change correlated with all haemodynamic parameters across all groups. Uteroplacental oxygen and glucose delivery were increased in LGUN compared to control ewes, whereas uteroplacental oxygen consumption was preserved. LGUN did not impact placental or fetal weight, and markers of brain-sparing physiology were absent. Placental expression of insulin-like growth factors (IGF-1 and IGF-2) and their receptors, glucose, fatty acid (FA) or amino acid transporters and markers of angiogenesis was not impacted. FA transporter expression was positively correlated with QUtA, and FA binding protein correlated negatively with maternal weight change. Maternal cardiovascular adaptations in response to LGUN manifest as preservation of placental growth and function, thereby preserving fetal growth. KEY POINTS: Maternal undernutrition during pregnancy alters fetal metabolic and cardiovascular physiology, but little is known about alterations in maternal haemodynamics. Late-gestation undernutrition (LGUN) and LGUN + G redirected maternal blood flow from the periphery to the uteroplacental unit, concomitantly increasing the delivery of glucose and oxygen to the uteroplacental unit. Substrate transporter expression and uteroplacental oxygen consumption were preserved in LGUN and LGUN + G, suggesting prioritization of the placenta. This study is the first to report detailed maternal haemodynamics in the setting of maternal undernutrition, where placental growth and function were maintained, ultimately preserving fetal oxygen metabolism and growth., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Babies born with fetal growth restriction (FGR) are at higher risk of developing cardiometabolic diseases across the life course. The reduction in substrate supply to the developing fetus that causes FGR not only alters cardiac growth and structure but may have deleterious effects on metabolism and function. Using a sheep model of placental restriction to induce FGR, we investigated key cardiac metabolic and functional markers that may be altered in FGR. We also employed phase-contrast magnetic resonance imaging MRI to assess left ventricular cardiac output (LVCO) as a measure of cardiac function. We hypothesized that signalling molecules involved in cardiac fatty acid utilisation and contractility would be impaired by FGR and that this would have a negative impact on LVCO in the late gestation fetus. Key glucose (GLUT4 protein) and fatty acid (FATP, CD36 gene expression) substrate transporters were significantly reduced in the hearts of FGR fetuses. We also found reduced mitochondrial numbers as well as abundance of electron transport chain complexes (complexes II and IV). These data suggest that FGR diminishes metabolic and mitochondrial capacity in the fetal heart; however, alterations were not correlated with fetal LVCO. Overall, these data show that FGR alters fetal cardiac metabolism in late gestation. If sustained ex utero, this altered metabolic profile may contribute to poor cardiac outcomes in FGR-born individuals after birth. KEY POINTS: Around the time of birth, substrate utilisation in the fetal heart switches from carbohydrates to fatty acids. However, the effect of fetal growth restriction (FGR) on this switch, and thus the ability of the fetal heart to effectively metabolise fatty acids, is not fully understood. Using a sheep model of early onset FGR, we observed significant downregulation in mRNA expression of fatty acid receptors CD36 and FABP in the fetal heart. FGR fetuses also had significantly lower cardiac mitochondrial abundance than controls. There was a reduction in abundance of complexes II and IV within the electron transport chain of the FGR fetal heart, suggesting altered ATP production. This indicates reduced fatty acid metabolism and mitochondrial function in the heart of the FGR fetus, which may have detrimental long-term implications and contribute to increased risk of cardiovascular disease later in life., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Fetal growth restriction (FGR) occurs in 8% of human pregnancies, and the growth restricted newborn is at a greater risk of developing heart disease in later adult life. In sheep, experimental restriction of placental growth (PR) from conception results in FGR, a decrease in cardiomyocyte endowment and an upregulation of pathological hypertrophic signalling in the fetal heart in late gestation. However, there is no change in the expression of markers of cellular proliferation nor in the level of cardiomyocyte apoptosis in the heart of the PR fetus in late gestation. This suggests that FGR arises early in gestation and programs a decrease in cardiomyocyte endowment in early, rather than late, gestation. Here, control and PR fetal sheep were humanely killed at 55 days' gestation (term, 150 days). Fetal body and heart weight were lower in PR compared with control fetuses and there was evidence of sparing of fetal brain growth. While there was no change in the proportion of cardiomyocytes that were proliferating in the early gestation PR heart, there was an increase in measures of apoptosis, and markers of autophagy and pathological hypertrophy in the PR fetal heart. These changes in early gestation highlight that FGR is associated with evidence of early cell death and compensatory hypertrophic responses of cardiomyocytes in the fetal heart. The data suggest that early placental restriction results in a decrease in the pool of proliferative cardiomyocytes in early gestation, which would limit cardiomyocyte endowment in the heart of the PR fetus in late gestation. KEY POINTS: Placental restriction leading to fetal growth restriction (FGR) and chronic fetal hypoxaemia in sheep results in a decrease in cardiomyocyte endowment in late gestation. FGR did not change cardiomyocyte proliferation during early gestation but did result in increased apoptosis and markers of autophagy in the fetal heart, which may result in the decreased endowment of cardiomyocytes observed in late gestation. FGR in early gestation also results in increased hypoxia inducible factor signalling in the fetal heart, which in turn may result in the altered expression of epigenetic regulators, increased expression of insulin-like growth factor 2 and cardiomyocyte hypertrophy during late gestation and after birth., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Metastable forms and amorphous forms exhibit higher solubility and dissolution rates compared to stable crystalline forms, making them viable options for pharmaceuticals with low solubility. However, the use of metastable forms and amorphous forms may result in polymorph transformation in pharmaceutical manufacture and storage, which will reduce their bioavailability. Firstly, different polymorphic transformations were discussed. Then, the factors affecting crystals and amorphous stability, including solvent, temperature, humidity, and preparation processes were analyzed. Finally, strategies and their mechanisms to inhibit polymorphic transformation and amorphous recrystallization were also summarized, including suitable storage conditions, optimization of the preparation processes, use of additives, adjustment of formulation recipes, and surface and loading techniques. [ABSTRACT FROM AUTHOR]

Considering climate change and the environmental pollution crisis, CO2-emission-free H2 production based on green, low-energy processes is critically important. In this article, we report the accidental discovery and subsequent investigation of room-temperature thermochemical water splitting in a planetary ball mill. H2 yields of ∼20–1600% were obtained by milling six metals (Al, Zn, Fe, Ti, Mn, and Sn) and their oxides in water at 30–38 °C. Remarkably, when Ti was milled, H2 was generated continuously until the water was consumed. Experimental and theoretical investigations—based on redox potentials, Gibbs energies, collision energies, and local temperatures and pressures—revealed that the milling medium acts as a mechano-cocatalyst, regenerating the catalyst (Ti and/or titanium oxides). Thus, thermochemical water splitting, via a cyclic mechanocatalytic TiO2/Ti–water reaction, was responsible for the continuous H2 production. The high H2-production rate was attributed to reactions occurring in supercritical water at impact sites between balls, where the instantaneous local pressure and temperature were 11 GPa and 1300 °C, respectively. The production of high-purity hydrogen (>99%) using seawater feedstocks in a compact (∼50 cm), low-power (∼0.26 kW) reactor indicates that on-site, on-demand H2 production is achievable. [ABSTRACT FROM AUTHOR]

Inspired by the scar‐free wound healing in infants, an anti‐scar strategy is proposed by accelerating wound healing using silicate bioactive materials. Bioglass/alginate composite hydrogels are applied, which significantly inhibit scar formation in rabbit ear scar models. The underlining mechanisms include stimulation of Integrin Subunit Alpha 2 expression in dermal fibroblasts to accelerate wound healing, and induction of apoptosis of hypertrophic scar fibroblasts by directly stimulating the N‐Acylsphingosine Amidohydrolase 2 expression in hypertrophic scar fibroblasts, and indirectly upregulating the secretion of Cathepsin K in dermal fibroblasts. Considering specific functions of the bioactive silicate materials, two scar treatment regimes are tested. For severe scars, a regenerative intervention is applied by surgical removal of the scar followed by the treatment with bioactive hydrogels to reduce the formation of scars by activating dermal fibroblasts. For mild scars, the bioactive dressing is applied on the formed scar and reduces scar by inducing scar fibroblasts apoptosis. [ABSTRACT FROM AUTHOR]

Radiation injuries, particularly those resulting from therapeutic or accidental exposure, present complex challenges for medical management. These injuries can manifest localized skin damage or extend to deeper tissues, presenting as various clinical entities that require treatment strategies, ranging from conservative management to complex surgical interventions. Radiation treatment constitutes a fundamental component of neoplastic management, with nearly two out of three oncological instances undergoing it as an element of their therapeutic strategy. The therapeutic approach to radiation injury consists of expanding prophylactic measures while maintaining the efficacy of treatment, such as conservative treatment or local debridement followed by reconstruction. The armamentarium of reconstructive methods available for plastic surgeons, from secondary healing to free tissue transfer, can be successfully applied to radiation injuries. However, the unique pathophysiological changes induced by radiation necessitate a careful and specialized approach for their application, considering the altered tissue characteristics and healing dynamics. The therapeutic strategy is guided by both the severity and progression of the injury, with the primary aim of restoring functionality and aesthetic aspects while simultaneously minimizing the risk of complications. This paper explores the various conditions encompassed by the term "radiation injury," reviews both non-surgical and surgical therapeutic strategies for managing these injuries, and highlights the unique challenges associated with treating irradiated tissues within specific oncological contexts. [ABSTRACT FROM AUTHOR]

The human primary visual cortex (V1) development is pivotal to understanding cortical maturation and neuroplasticity. Theories on V1 development range from early maturation models, which emphasize the early peak of synapses in infancy, to those suggesting an extended developmental timeline where key plasticity mechanisms continue to mature well into adulthood. Classic histological approaches have supported early development, while recent molecular studies highlight prolonged or multiple windows of plasticity, indicating that V1 remains susceptible to experience-dependent modifications beyond childhood. This review consolidates findings from both anatomical and molecular studies, tracing the development of V1 from prenatal stages through aging. The evidence reveals that human V1 develops across multiple timescales, with some aspects maturing early and others gradually changing across the lifespan. Reflecting on Cajal’s early work, this review underscores the importance of methodological advancements in revealing the intricate details of V1’s development. [ABSTRACT FROM AUTHOR]

The editorial discusses interventions for students with combined learning and behavioral difficulties, emphasizing the complex relationships between academic skills deficits and behavior problems. The editorial highlights the need for effective interventions to support affected students and the importance of research into the development of corresponding interventions. It also addresses the lack of intervention studies focusing on students with combined learning and behavior difficulties, underscoring the necessity for more research in this area to improve academic outcomes and behavior for these students. [Extracted from the article]