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Abstract Gilles de la Tourette Syndrome (GTS) is a chronic tic disorder, characterized by unwanted motor actions and vocalizations. While brain stimulation techniques show promise in reducing tic severity, optimal target networks are not well-defined. Here, we leverage datasets from two independent deep brain stimulation (DBS) cohorts and a cohort of tic-inducing lesions to infer critical networks for treatment and occurrence of tics by mapping stimulation sites and lesions to a functional connectome derived from 1,000 healthy participants. We find that greater tic reduction is linked to higher connectivity of DBS sites (N = 37) with action-related functional resting-state networks, i.e., the cingulo-opercular (r = 0.62; p

Purpose: Acute appendicitis (AA), classified as non-complicated acute appendicitis (NCAA) and complicated acute appendicitis (CAA), is the most common cause of abdominal pain in children requiring surgical treatment. If the first-line treatment for NCAA is to be debated between conservative management and surgery, authors find a consensus in choosing surgery as the first step for CAA in children. In the case of patients with CAA undergoing surgery, a broad-spectrum antibiotic therapy should be administered to reduce the risk of post-operative complications (POC). The rise in antibiotic resistance requires a review of recent data regarding bacterial species involved in AA. The primary aim of our study was to investigate the clinical effectiveness of different antibiotic protocols in patients undergoing surgery for CAA. The secondary aim was to verify the antibiotic’s in vitro effectiveness based on cultural examinations. Methods: A retrospective and prospective study was conducted on all patients operated on at our pediatric surgery department for CAA from January 2017 to January 2023. The following data were collected: age at surgery, sex, surgical technique, duration of the procedure, antibiotic therapy, duration of the hospital stay, cultural examination of peritoneal effusion, and POC. Results: We divided the patients enrolled (n = 182) into three groups of antibiotic protocols; only one group resulted in a statistically significant lower rate of POC. Different pathogens were isolated (Enterobacteriaceae, non-fermentative Gram-negative bacilli, anaerobes, Gram-positive cocci), and the in vitro rate of antimicrobial sensitivity varied from 40% to 94% in the three groups of patients. Conclusions: Based on cultural examinations, our study showed a high rate of inadequacy regarding the therapy with amoxicillin + clavulanic acid despite a low rate of complications. Radical surgery seems to be the best way to reduce complications in children with CAA.

Abstract Surgical repair of abdominal aortic aneurism (AAA) with horseshoe kidney (HK) is challenging because of several accessory renal arteries (RAs), variable in number, branches, and vascular territories, with subsequent variable renal damage. The identification of RAs and vascular territories could contribute to surgical planning. We developed a semiautomatic presurgical computed tomography angiography (CTA)-based model to measure the renal volume of each RA, validated on postsurgical CTA in patients with HK treated for AAA. Renal parenchyma volume was extracted on both CTAs (Vol_Totpre and Vol_Totpost) after labeling RAs ostia and vascular endpoints by two observers using a semiautomatic model by assigning each renal voxel to the closest vascular ending, obtaining volumes for each vascular territory. Number of RAs number was 4.0 ± 1.4 (mean ± standard deviation (SD)), Vol_Totpre 360 ± 76.5 cm3; kidney volume loss at surgery (KVLS) (Vol_Totpre minus Vol_Totpost) 51.9 ± 35.4 cm3; percentage of kidney loss 15.2 ± 11.6%. KVLS and predicted kidney volume loss on preoperative CTA (PKVL) were strongly correlated (r = 0.93; p = 0.023). Interobserver agreement was good (mean bias = 0.000001 ± 1.96 SD of 19.1 cm3). Presurgical semiautomatic segmentation of vascular territories in patients with HK and AAA is feasible. Relevance statement This software allowed the preoperative calculation of renal volume perfused by each renal artery in the challenging association of the horseshoe kidney and abdominal aortic aneurism. It helps to determine the feasibility of surgical resection of arteries, thereby improving surgical planning and reducing the risk of postoperative renal function deterioration. Key Points The association between horseshoe kidney and abdominal aortic aneurism is a challenging condition that may require renal vascular resection. A semiautomatic model measures renal volume perfused by each artery on preoperative computed tomography angiography with high accuracy. Customized use of this tool could improve surgical management by determining which arteries can be safely resected during surgery. Graphical Abstract

Abstract The low-latitude habitats of the South American reef system have a high endemism and represent important stepping-stones due to the connectivity with Amazon and Caribbean reefs. We provide the first seabed mapping, and analyze the benthic cover and fish assemblages of these extreme reefs. Fleshy macroalgae (2—66% of cover), algal turfs (0—47%), and sponges (3—25%) are the dominant benthic groups. The main reef builders are crustose coralline algae (2—23%) and only four coral species (0 to 18%), mainly the weedy Siderastrea stellata. Cluster analysis distinguished two groups. The first group includes the shallowest reefs (~ 17 m deep) where fleshy macroalgae are abundant together with higher siltation on the reefs (~ 31% covered by sediments). The second group, by contrast, includes the deeper reefs (22.5—27 m), which have much higher algal turf cover, and the lowest sediment cover (4%). The deeper reefs also have the highest cover of corals (18%) and sponges (25%). We recorded a total of 63 fish species, with the deep reefs being the richest. Analysis indicated that the composition of the benthos was considerably more homogeneous across the study area than the composition of fish assemblages, which had a higher turnover of species among reefs. Moreover, we identified the depth of the reef as a variable structuring the benthic assemblages. The fish assemblage is influenced, in turn, by the benthos. Overall, the seabed mapping revealed the existence of a single reef system with high spatial heterogeneity. Our results provide new insights into the structure of these extreme reefs that have evolved under the influence of sediment resuspension, moderate turbidity, and are warmer than other West Atlantic reefs located at middle- and high-latitudes.

Introduction: With the advancements in chemotherapy for malignant bone tumors, the number of patients eligible for limb salvage surgery has increased. Surgeons face a subsequent challenge in limb-sparing resection due to the need for reconstructing soft tissue coverage. The aim of this review is to focus on the present state of the field in these areas, highlighting recent advancements. Methods: A literature research was conducted using keywords such as “soft tissue”, “integration”, “reconstruction”, “megaprosthesis”, and “soft tissue coverage”, on different databases, and following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria, a total of 35 studies were selected. Results: In recent times, there has been a growing emphasis on different techniques such mesh application, allograft-prosthesis composites, allograft reconstruction, a polyethylene terephthalate (PET) tube, prosthesis itself and certain metals utilized for implant coatings are used in soft tissue reconstruction. Conclusion: While tissue-engineered constructs and advancements in biological and cellular approaches have shown potential for enhancing osseointegration and interactions with soft tissues and implants, the actual clinical outcomes have frequently fallen short of expectations. The success of soft tissue integration is crucial for achieving functional outcomes, minimizing complications, and ensuring the long-term stability of orthopedic implants.

Abstract MicroRNAs (miRNAs) play dual roles in acute lymphoblastic leukemia (ALL) as both tumor suppressors and oncogenes, and miRNA expression profiles can be used for patient risk stratification. Precise assessment of miRNA levels is crucial for understanding their role and function in gene regulation. Quantitative real-time polymerase chain reaction (qPCR) is a reliable, rapid, and cost-effective method for analyzing miRNA expression, assuming that appropriate normalization to stable references is performed to ensure valid data. In this study, we evaluated the stability of six commonly used miRNA references (5sRNA, SNORD44, RNU6, RNU1A1, miR-103a-3p, and miR-532-5p) across nine B-cell precursor (BCP) ALL cell lines, 22 patient-derived xenograft (PDX) BCP ALL samples from different organ compartments of leukemia bearing mice, and peripheral blood mononuclear cells (PBMCs) from six healthy donors. We used four different algorithms (Normfinder, ∆CT, geNorm, and BestKeeper) to assess the most stably expressed reference across all samples. Moreover, we validated our data in an additional set of 13 PDX ALL samples and six healthy controls, identifying miR-103a-3p and miR-532-5p as the most stable references for miRNA normalization in BCP ALL studies. Additionally, we demonstrated the critical importance of using a stable reference to accurately interpret miRNA data.

Abstract Focal liver lesions are frequently encountered during imaging studies, and hemangiomas represent the most common solid liver lesion. Liver hemangiomas usually show characteristic imaging features that enable characterization without the need for biopsy or follow-up. On the other hand, there are many benign and malignant liver lesions that may show one or more imaging features resembling hemangiomas that radiologists must be aware of. In this article we will review the typical imaging features of liver hemangiomas and will show a series of potential liver hemangiomas’ mimickers, giving radiologists some hints for improving differential diagnoses. Critical relevance statement The knowledge of imaging features of potential liver hemangiomas mimickers is fundamental to avoid misinterpretation. Key Points Liver hemangiomas typically show imaging features that enable avoiding a biopsy. Many benign and malignant liver lesions show imaging features resembling hemangiomas. Radiologists must know the potentially misleading imaging features of hemangiomas’ mimickers. Graphical Abstract

Abstract We present SMEFiT3.0, an updated global SMEFT analysis of Higgs, top quark, and diboson production data from the LHC complemented by electroweak precision observables (EWPOs) from LEP and SLD. We consider recent inclusive and differential measurements from the LHC Run II, alongside with a novel implementation of the EWPOs based on independent calculations of the relevant EFT contributions. We estimate the impact of HL-LHC measurements on the SMEFT parameter space when added on top of SMEFiT3.0, through dedicated projections extrapolating from Run II data. We quantify the significant constraints that measurements from two proposed high-energy circular e + e − colliders, the FCC-ee and the CEPC, would impose on both the SMEFT parameter space and on representative UV-complete models. Our analysis considers projections for the FCC-ee and the CEPC based on the latest running scenarios and includes Z-pole EWPOs, fermion-pair, Higgs, diboson, and top quark production, using optimal observables for both the W + W − and the t t ¯ $$ t\overline{t} $$ channels. The framework presented in this work may be extended to other future colliders and running scenarios, providing timely input to ongoing studies towards future high-energy particle physics facilities.

Abstract The increase in the construction of mega dams in tropical basins is considered a threat to freshwater fish diversity. Although difficult to detect in conventional monitoring programs, rheophilic species and those reliant on shallow habitats comprise a large proportion of fish diversity in tropical basins and are among the most sensitive species to hydropower impacts. We used Baited Remote Underwater Video (BRUV), an innovative, non-invasive sampling technique, to record the impacts caused by Belo Monte, the third largest hydropower project in the world, on fishes inhabiting fast waters in the Xingu River. BRUV were set in a river stretch of ~ 240 km for 7 years, 2 before and 5 after the Belo Monte operation. We explored the spatial and temporal variation in fish diversity (α, β, and γ) and abundance (MaxN) using generalized additive models. We also investigated the variation of environmental variables and tested how much information we gained by including them in the diversity and abundance models. Belo Monte altered the flow regime, water characteristics, and fishery yield in the Xingu, resulting in changes in the fish community structure. Temporally, we observed sharp declines in α diversity and abundance, far exceeding those from a previous study conducted with more conventional sampling methods (i.e., catch-based) in the region. γ-diversity was also significantly reduced, but we observed a non-expected increase in β diversity over time. The latter may be associated with a reduction in river connectivity and an increase in environmental heterogeneity among river sectors. Unexpected signs of recovery in diversity metrics were observed in the last years of monitoring, which may be associated with the maintenance of flow levels higher than those previously planned. These results showed that BRUV can be a useful and sensitive tool to monitor the impacts of dams and other enterprises on fish fauna from clear-water rivers. Moreover, this study enhances our comprehension of the temporal variations in freshwater fish diversity metrics and discusses the prevalent assumption that a linear continuum in fish-structure damage associated with dam impoundments may exhibit temporal non-linearity.

Background: Catheter-directed treatment (CDT) is an innovative treatment for patients with elevated risk pulmonary embolism (PE) to resolve embolus and restore pulmonary perfusion. Objectives: We aimed to analyse the use and the benefit of CDT in PE patients in Germany. Methods: The German nationwide inpatient sample was used to include all hospitalizations of patients with PE from 2005 to 2020 in Germany. PE patients were stratified for CDT usage. Temporal trends and the impact of CDT on case fatality and other outcomes were investigated. Results: Overall, 1,373,084 hospitalizations of patients with PE (55.9% aged ≥70 years; 53.0% females) were included in this study from 2005 to 2020, and among these, 427,238 (31.1%) patients were categorized as having elevated-risk PE and 3330 (0.2%) were treated with CDT with annual increase from 0.17% (2005) to 0.51% (2020). PE patients of younger age, male sex, with previous surgery, and elevated-risk PE were more often treated with CDT. In patients with elevated risk-PE, CDT attributed to a lower observed rate of major adverse cardiac and cerebrovascular events (major adverse cardiac and cerebrovascular events [MACCE]; 28.2% vs 34.2%; P < .001) and in-hospital case fatality (24.9% vs 31.0%; P < .001). CDT was associated with reduced MACCE (OR, 0.91; 95% CI, 0.83-0.99) and with a trend toward lower case fatality (OR, 0.92; 95% CI, 0.84-1.01). The benefit of CDT regarding case fatality was age-dependent. Conclusion: Although the annual rate of CDT increased in Germany between 2005 and 2020, only 0.2% of the PE patients were treated with CDT. Selection criteria for CDT treatment were younger age, male sex, previous surgery, and elevated risk-PE. CDT treatment was associated with reduced MACCE and case-fatality rate in PE patients with elevated-risk PE.

Introduction Healthcare practices providing minimal or no benefit to recipients have been estimated to represent 20% of healthcare costs. However, defining, measuring and monitoring low-value care (LVC) and its downstream consequences remain a major challenge. The purpose of the National Data Stream (LUCID NDS) is to identify and monitor LVC in medical inpatients using routinely collected hospital data.Methods and analysis This protocol describes a multistep approach to the identification and surveillance of LVC: (1) creating an NDS based on Findable, Accessible, Interoperable, Reusable (FAIR) principles using routinely collected hospital data from medical inpatients who signed a general consent for data reuse from 2014 onwards; (2) selecting recommendations applicable to medical inpatients using data from LUCID NDS to develop a comprehensive and robust set of LVC indicators; (3) establishing expert consensus on the most relevant and actionable recommendations to prevent LVC; (4) applying the Strength of Recommendation Taxonomy methodology to assess the level of evidence of recommendations; (5) involving patients and the public at various stages of LUCID NDS; and (6) designing monitoring rules within the LUCID NDS and validating quality measures.Ethics and dissemination The ethics committees of all five participating university hospitals (Basel, Bern, Geneva, Lausanne and Zurich) approved LUCID NDS as a national registry on quality of care. We will disseminate our findings in peer-reviewed journals, at professional conferences, and through short reports sent to participating entities and stakeholders; moreover, lay summaries are provided for patients and the broader public on our webpage (www.LUCID-nds.ch).

Objective: To help healthcare professionals (HCP) act with more confidence when communicating about approaching death, we sought to develop a communication model for HCP to facilitate conversations with dying patients and family caregivers (FC) in nonemergency situations. Methods: We used a four-phase integrative approach: (1) creation of a preliminary model based on a systematic literature review and expert knowledge, (2) review of the model draft by international palliative care experts, (3) review by key stakeholders, and (4) final appraisal by communication experts. Results: After the clinical recognition of dying, the communication model provides a structure and practical communication aids for navigating the conversation based on three phases. It describes the content and relational level as core dimensions of effective conversations about approaching death and highlights the importance of HCP self-awareness and self-care when caring for the dying. Conclusion: Based on systematic involvement of key stakeholders, the model supports clinicians navigating challenging conversations about approaching death with dying patients and their FC successfully and with more confidence. Innovation: This study expands the theoretical basis for communication about approaching death and offers a pragmatic model for educational interventions and clinical use.

Abstract Objective No direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse‐associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register. Methods Patients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score‐matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan–Meier curves were used to show cumulative probabilities of reaching outcomes. Results In total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score‐matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab‐ and 10 ocrelizumab‐treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab‐ and 15 ocrelizumab‐treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59–1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57–2.66; p = 0.60) and 6.0 (0.93, 0.32–2.68; p = 0.89). Interpretation Both medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different.

Abstract We discuss a Bayesian methodology for the solution of the inverse problem underlying the determination of parton distribution functions (PDFs). In our approach, Gaussian processes (GPs) are used to model the PDF prior, while Bayes’ theorem is used in order to determine the posterior distribution of the PDFs given a set of data. We discuss the general formalism, the Bayesian inference at the level of both parameters and hyperparameters, and the simplifications which occur when the observable entering the analysis is linear in the PDF. We benchmark the new methodology in two simple examples for the determination of a single PDF flavor from a set of deep inelastic scattering (DIS) data and from a set of equal-time correlators computed using lattice QCD. We discuss our results, showing how the proposed methodology allows for a well-defined statistical interpretation of the different sources of errors entering the PDF uncertainty, and how results can be validated a posteriori.

Abstract We extend the existing leading (LO), next-to-leading (NLO), and next-to-next-to-leading order (NNLO) NNPDF4.0 sets of parton distribution functions (PDFs) to approximate next-to-next-to-next-to-leading order ( $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO ). We construct an approximation to the $$\hbox {N}^3\hbox {LO}$$ N 3 LO splitting functions that includes all available partial information from both fixed-order computations and from small and large x resummation, and estimate the uncertainty on this approximation by varying the set of basis functions used to construct the approximation. We include known $$\hbox {N}^3\hbox {LO}$$ N 3 LO corrections to deep-inelastic scattering structure functions and extend the FONLL general-mass scheme to $$\mathcal {O}\left( \alpha _s^3\right) $$ O α s 3 accuracy. We determine a set of $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO PDFs by accounting both for the uncertainty on splitting functions due to the incomplete knowledge of $$\hbox {N}^3\hbox {LO}$$ N 3 LO terms, and to the uncertainty related to missing higher corrections (MHOU), estimated by scale variation, through a theory covariance matrix formalism. We assess the perturbative stability of the resulting PDFs, we study the impact of MHOUs on them, and we compare our results to the $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO PDFs from the MSHT group. We examine the phenomenological impact of $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO corrections on parton luminosities at the LHC, and give a first assessment of the impact of $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO PDFs on the Higgs and Drell–Yan total production cross-sections. We find that the $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO NNPDF4.0 PDFs are consistent within uncertainties with their NNLO counterparts, that they improve the description of the global dataset and the perturbative convergence of Higgs and Drell–Yan cross-sections, and that MHOUs on PDFs decrease substantially with the increase of perturbative order.

By means of relaxation methods, residual stresses can be obtained by introducing a progressive cut or a hole in a specimen and by measuring and elaborating the strains or displacements that are consequently produced. If the cut can be considered a controlled crack-like defect, by leveraging Bueckner’s superposition principle, the relaxed strains can be modeled through a weighted integral of the residual stress relieved by the cut. To evaluate residual stresses, an integral equation must be solved. From a practical point of view, the solution is usually based on a discretization technique that transforms the integral equation into a linear system of algebraic equations, whose solutions can be easily obtained, at least from a computational point of view. However, the linear system is often significantly ill-conditioned. In this paper, it is shown that its ill-conditioning is actually a consequence of a much deeper property of the underlying integral equation, which is reflected also in the discretized setting. In fact, the original problem is ill-posed. The ill-posedness is anything but a mathematical sophistry; indeed, it profoundly affects the properties of the discretized system too. In particular, it induces the so-called bias–variance tradeoff, a property that affects many experimental procedures, in which the analyst is forced to introduce some bias in order to obtain a solution that is not overwhelmed by measurement noise. In turn, unless it is backed up by sound and reasonable physical assumptions on some properties of the solution, the introduced bias is potentially infinite and impairs every uncertainty quantification technique. To support these topics, an illustrative numerical example using the crack compliance (also known as slitting) method is presented. The availability of the Linear Elastic Fracture Mechanics Weight Function for the problem allows for a completely analytical formulation of the original integral equation by which bias due to the numerical approximation of the physical model is prevented.

IntroductionCrocodilians have significant ecological, conservational, and economic roles. They are also commonly raised for commercial purposes and kept as zoological specimens. Although ultrasonography has been used in zoological contexts for health assessments of crocodilians, published studies on a detailed ultrasonography protocol and ultrasonographic anatomy are lacking. This study aimed to establish a standardized ultrasonography protocol and pictorial reference of the ultrasonographic appearances of the coelomic organs of crocodilians.MethodsA total of 7 crocodilians comprising 4 different species were included in this study. The crocodilians were manually restrained and underwent a non-contrasted and contrasted computed tomography (CT) scan, followed by an ultrasonography (USG) examination. Ultrasound fusion imaging technique enabled greater confidence in establishing a clear organ localization and correlation between modalities by visualizing the same anatomy from the same view angle.ResultsThe heart, caudal vena cava, liver, fat body (steatotheca), spleen, stomach, duodenal loops, pancreas, kidneys, testes, ovaries and cloaca were visualized in all species. Longitudinal and transverse images of the coelomic structures were acquired when possible. The ultrasonographic characteristics of the coelomic organs, including transducer positioning, acoustic window and approach, shape, size, marginations, and echo pattern were documented.DiscussionThe findings of this study provided a useful ultrasonographic protocol and anatomical reference of the coelomic organs in crocodilians. Invaluable insights into the practicality and adequacy of ultrasonography in evaluating the coelomic structures of crocodilians as part of health assessment and disease diagnosis were also discussed.

Abstract Knowledge regarding the early life history of neotropical fish, although incipient, is crucial for the accurate identification of larvae collected from the natural environment. Such details are important for defining spawning, drift, and nursery areas as well as the reproductive periods of species. Herein, the larval development of Cynodon gibbus was described using morphological, meristic, and morphometric characteristics. Specimens were collected from open water limnetic zones and under macrophyte stands in the Amazon basin from 2010 to 2023. Forty-eight larvae with standard lengths ranging from 5.73 to 21.57 mm were studied. The larvae have a long to very long body, small eyes, and a small head, which progresses to a moderate size in the preflexion stage. Furthermore, the larvae had ample mouths with numerous conical teeth, an oval-triangular swim bladder, overlapping dorsal and anal fins, and the tip of the pectoral fin not reaching the swim bladder. Pigmentation pattern comprised two punctate pigments above the fontanelle, the rectum, and at the lower and upper ends of the caudal peduncle. Various body parts exhibited predominant allometric relationships, reflecting differential developmental rates among them in response to fundamental ecological requirements for survival. The C. gibbus larvae can be identified by a combination of the position of dorsal, anal and pectoral fins, pigmentation pattern, swim bladder shape, and the total number of myomeres (51 to 53).

IntroductionBisphenol A (BPA) is a common contaminant widely used in many industrial sectors. Because of its wide use and dispersion, it can be accumulated in living human bodies through both oral assumption and nondietary routes. BPA exhibits hormone-like properties, falling under the class of endocrine disruptors; therefore, it can alter relevant physiological functions. In particular, in women, it can affect folliculogenesis and therefore reproduction, contributing not only to infertility, but also to endometriosis and premature puberty.MethodsWe conducted a multicenter study on 91 women undergoing a first in vitro fertilization (IVF) treatment in the Campania region (Southern Italy). We investigated the presence and concentration of BPA in serum and follicular fluids to assess the effects of airborne BPA contamination. The analysis was conducted on 32 women living in a low environmental impact (LEI) area, from the Sele Valley River and Cilento region, and 59 women living in a high environmental impact (HEI) area, the so-called “Land of Fires”, a highly contaminated territory widely exposed to illegal waste practices.ResultsA higher average BPA content in both blood serum and follicular fluid was revealed in the HEI group when compared with the LEI group. In addition, we revealed higher average BPA content in blood serum than in folliclular fluid in the HEI area, with opposite average content in the two fluids in the LEI zone. In addition, our results also showed a lack of correlation between BPA content in follicular and serum fluids both in the overall population and in the HEI and LEI groups, with peculiar trends in different subsets of women.ConclusionFrom our results, we revealed a heterogeneity in the distribution of BPA content between serum and follicular fluid. Further studies are needed to unravel the bioaccumulation mechanisms of BPA in highly polluted and nonpolluted areas.

Oases are vulnerable ecosystems that are affected by climate change. Using high-resolution climate models focusing on northern Africa, we investigate the changes in the agrosystems of oases. Projected air temperature changes under an extreme global warming scenario are statistically significant for all oases studied, with an increase of up to 4–4.5 °C by the end of the century. The impact of the projected warming is likely to lead to an increased groundwater demand, with a parallel trend in reduced precipitation. Combined, these processes endanger the long-term socio-economic prospect of oases.

Nasogastric Tubes (NGT) are widely used in hospitals, e.g. for the administration of nutrients or drugs and gastric release after major surgeries. Blind insertion of these tubes is usually performed by nurses, residents, and other health care providers. In this case report, we present an incident of misplacement of the NGT, located in the pleural space, and causing pneumothorax. NGT can be inserted accidentally into the airways leading to complications like pneumonia, pneumothorax, and even death. Mechanically ventilated patients are at high risk of having an NGT misplaced, since they often have reduced consciousness and weak cough reflex.

Abstract We include uncertainties due to missing higher order corrections to QCD computations (MHOU) used in the determination of parton distributions (PDFs) in the recent NNPDF4.0 set of PDFs. We use our previously published methodology, based on the treatment of MHOUs and their full correlations through a theory covariance matrix determined by scale variation, now fully incorporated in the new NNPDF theory pipeline. We assess the impact of the inclusion of MHOUs on the NNPDF4.0 central values and uncertainties, and specifically show that they lead to improved consistency of the PDF determination. PDF uncertainties on physical predictions in the data region are consequently either unchanged or moderately reduced by the inclusion of MHOUs.

Abstract We construct a set of parton distribution functions (PDFs), based on the recent NNPDF4.0 PDF set, that also include a photon PDF. The photon PDF is constructed using the LuxQED formalism, while QED evolution accounting for $${\mathcal {O}}\left( \alpha \right) $$ O α , $${\mathcal {O}}\left( \alpha \alpha _s\right) $$ O α α s , and $${\mathcal {O}}\left( \alpha ^2\right) $$ O α 2 corrections is implemented and benchmarked by means of the EKO code. We investigate the impact of QED effects on NNPDF4.0, and compare our results both to our previous NNPDF3.1QED PDF set and to other recent PDF sets that include the photon. We assess the impact of photon-initiated processes and electroweak corrections on a variety of representative LHC processes, and find that they can reach the 5% level in vector boson pair production at large invariant mass.

Abstract Proton-proton collisions at the LHC generate a high-intensity collimated beam of neutrinos in the forward (beam) direction, characterised by energies of up to several TeV. The recent observation of LHC neutrinos by FASER $$\nu $$ ν and SND@LHC signifies that this previously overlooked particle beam is now available for scientific investigation. Here we quantify the impact that neutrino deep-inelastic scattering (DIS) measurements at the LHC would have on the parton distributions (PDFs) of protons and heavy nuclei. We generate projections for DIS structure functions for FASER $$\nu $$ ν and SND@LHC at Run III, as well as for the FASER $$\nu $$ ν 2, AdvSND, and FLArE experiments to be hosted at the proposed Forward Physics Facility (FPF) operating concurrently with the High-Luminosity LHC (HL-LHC). We determine that up to one million electron-neutrino and muon-neutrino DIS interactions within detector acceptance can be expected by the end of the HL-LHC, covering a kinematic region in x and $$Q^2$$ Q 2 overlapping with that of the Electron-Ion Collider. Including these DIS projections in global (n)PDF analyses, specifically PDF4LHC21, NNPDF4.0, and EPPS21, reveals a significant reduction in PDF uncertainties, in particular for strangeness and the up and down valence PDFs. We show that LHC neutrino data enable improved theoretical predictions for core processes at the HL-LHC, such as Higgs and weak gauge boson production. Our analysis demonstrates that exploiting the LHC neutrino beam effectively provides CERN with a “Neutrino-Ion Collider” without requiring modifications in its accelerator infrastructure.

Abstract We define bipartite and monopartite relational networks of chemical elements and compounds using two different datasets of inorganic chemical and material compounds, as well as study their topology. We discover that the connectivity between elements and compounds is distributed exponentially for materials, and with a fat tail for chemicals. Compounds networks show similar distribution of degrees, and feature a highly-connected club due to oxygen . Chemical compounds networks appear more modular than material ones, while the communities detected reveal different dominant elements specific to the topology. We successfully reproduce the connectivity of the empirical chemicals and materials networks by using a family of fitness models, where the fitness values are derived from the abundances of the elements in the aggregate compound data. Our results pave the way towards a relational network-based understanding of the inherent complexity of the vast chemical knowledge atlas, and our methodology can be applied to other systems with the ingredient-composite structure.

Abstract The study aims at investigating the use of reflectance Hyperspectral Imaging (HSI) in the Visible (Vis) and Near Infrared (NIR) range in combination with Deep Convolutional Neural Networks (CNN) to address the tasks related to ancient Egyptian hieroglyphs recognition. Recently, well-established CNN architectures trained to address segmentation of objects within images have been successfully tested also for trial sets of hieroglyphs. In real conditions, however, the surfaces of the artefacts can be highly degraded, featuring corrupted and scarcely readable inscriptions which highly reduce the CNNs capabilities in automated recognition of symbols. In this study, the use of HSI technique in the extended Vis-NIR range is proposed to retrieve readability of degraded symbols by exploiting spectral images. Using different algorithmic chains, HSI data are processed to obtain enhanced images to be fed to the CNN architectures. In this pilot study, an ancient Egyptian coffin (XXV Dynasty), featuring a degraded hieroglyphic inscription, was used as a benchmark to test, in real conditions, the proposed methodological approaches. A set of Vis-NIR HSI data acquired on-site, in the framework of a non-invasive diagnostic campaign, was used in combination with CNN architectures to perform hieroglyphs segmentation. The outcomes of the different methodological approaches are presented and compared to each other and to the results obtained using standard RGB images.

At first sight Benjamin’s thought reveals many themes in common with Leopardi’s philosophy and, above all, it shows the same critical perspective toward contemporary models. This paper intends to explore this common ground, studying especially the analysis that Leopardi and Benjamin dedicated to the work of art: since both looked with disillusion at the European cultural environment, it’s just natural that the questions around the work of art and its reception occupy a fundamental role in their thoughts. In this perspective, Leopardi’s meditation seems on the same page of Benjamin’s most famous work, The work of art in the age of mechanical reproduction: studying the deep contradiction between the aura of «opere di genio» and the trace of an acritical work of art, this paper tries to investigate some key points of Leopardi’s thought, like the role of the image (and so, of the imagination) within Zibaldone’s gnoseological structure, and the phylogenetical propriety of «immagini antiche».

Abstract We revisit our argument that shows that parton distribution functions (PDFs) in the $$\overline{\textrm{MS}}$$ MS ¯ scheme are non-negative in the perturbative region, with the dual goals of clarifying its theoretical underpinnings and elucidating its domain of validity. We specifically discuss recent results proving that PDFs can turn negative at sufficiently low scale, we clarify quantitatively various aspects of our derivation of positivity in the perturbative region, and we provide an estimate for the scale above which PDF positivity holds.

Heterogeneous and complex networks represent intertwined interactions between real-world elements or agents. Determining the multiscale mesoscopic organization of clusters and intertwined structures is still a fundamental and open problem of complex network theory. By taking advantage of the recent Laplacian renormalization group (LRG), we scrutinize information diffusion pathways throughout networks to shed further light on this issue. Based on internode communicability, our definition provides a clear-cut framework for resolving the multiscale mesh of structures in complex networks, disentangling their intrinsic arboreal architecture. As it does not consider any topological null-model assumption, the LRG naturally permits the introduction of scale-dependent optimal partitions. Moreover, we demonstrate the existence of a particular class of nodes, called metastable nodes, that switch regions to which they belong at different scales, likely playing a pivotal role in cross-regional communication and, therefore, in managing macroscopic effects of the whole network.

Background: In pediatric surgery, a comprehensive knowledge of the child’s anatomy is crucial to optimize surgical outcomes and minimize complications. Recent advancements in medical imaging and technology have introduced innovative tools that enhance surgical planning and decision-making. Methods: This study explores the integration of mixed reality technology, specifically the HoloLens 2 headset, for visualization and interaction with three-dimensional (3D) anatomical reconstructions obtained from computed tomography (CT) scans. Our prospective observational study, conducted at IRCCS (Scientific Hospitalization and Care Institute) Sant’Orsola-Malpighi University Hospital in Bologna, engaged ten pediatric surgeons, who assessed three types of anatomical malformations (splenic cysts, pulmonary cystic adenomatoid malformations, and pyelo-ureteral junction stenosis) and planned surgeries using both traditional 2D CT scans and 3D visualizations via HoloLens 2, followed by completing a questionnaire to evaluate the utility of each of these imaging techniques in surgical planning. Results: The statistical analysis revealed that the 3D visualizations significantly outperformed the 2D CT scans in clarity and utility (p < 0.05). The results indicated significant improvements in anatomy understanding and surgical precision. The immersive experience provided by HoloLens 2 enabled surgeons to better identify critical landmarks, understand spatial relationships, and prevent surgical challenges. Furthermore, this technology facilitated collaborative decision-making and streamlined surgical workflows. Conclusions: Despite some challenges in ease of use, HoloLens 2 showed promising results in reducing the learning curve for complex procedures. This study underscores the transformative potential of mixed reality technology in pediatric surgery, advocating for further research and development to integrate these advancements into routine clinical practice.

Background: Diabetic foot ulcers are a common complication of diabetes mellitus, often leading to progressive sensory deficits, impaired vascularization, and a predisposition to ulceration and gangrene. Untreated ulcers may cause recurrent infections that endanger a patient’s life. Amputation of part of the limb up to a well-vascularized level is one of the treatments employed for untreated ulcers. Objectives: Laboratory data were analyzed with the aim of identifying risk factors related to surgical amputation treatment of diabetic foot. We believe it is useful to identify risk factors that can be altered from a reversible condition in the clinical decision-making of treatment, thus manifesting themselves in a timely manner to provide the patient with an alternative to surgical amputation of the lower limb. Methods: Our retrospective study was conducted by the Department of Orthopedics and Traumatology at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome. We recruited 200 patients who underwent lower limb amputation for diabetic foot between 2017 and 2021 and had blood tests both 30 days and within 5 days before the first surgery. Results: This case–control study revealed a significant negative correlation between hemoglobin (Hb) levels and the occurrence of leg amputations. In contrast, C-reactive protein (CRP) levels, the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR) showed significant positive correlations with leg amputations. A 3-year follow-up of the cases also revealed a significative positive correlation between age, white blood cells (WBC) count, NLR, PLR, and death at 3 years. Conclusions: Our findings suggested that lower Hb levels and elevated CRP, NLR, and PLR levels in patients with diabetic foot disease may be associated with a higher risk of lower-limb amputation. Unexpectedly, this study also demonstrated that elderly age, WBC, CRP, NLR and PLR levels may be associated with a negative prognosis for these patients. These findings highlighted the importance of monitoring these laboratory values in diabetic patients to identify individuals at higher risk of leg amputations and implement appropriate interventions to prevent or minimize the occurrence of this severe complication.

Summary: Background: The search for factors beyond the radiotherapy dose that could identify patients more at risk of developing radio-induced toxicity is essential to establish personalised treatment protocols for improving the quality-of-life of survivors. To investigate the role of the intestinal microbiota in the development of radiotherapy-induced gastrointestinal toxicity, the MicroLearner observational cohort study characterised the intestinal microbiota of 136 (discovery) and 79 (validation) consecutive prostate cancer patients at baseline radiotherapy. Methods: Gastrointestinal toxicity was assessed weekly during RT using CTCAE. An average grade >1.3 over time points was used to identify patients suffering from persistent acute toxicity (endpoint). The microbiota of patients was quantified from the baseline faecal samples using 16S rRNA gene sequencing technology and the Ion Reporter metagenomic pipeline. Statistical techniques and computational and machine learning tools were used to extract, functionally characterise, and predict core features of the bacterial communities of patients who developed acute gastrointestinal toxicity. Findings: Analysis of the core bacterial composition in the discovery cohort revealed a cluster of patients significantly enriched for toxicity, displaying a toxicity rate of 60%. Based on selected high-risk microbiota compositional features, we developed a clinical decision tree that could effectively predict the risk of toxicity based on the relative abundance of genera Faecalibacterium, Bacteroides, Parabacteroides, Alistipes, Prevotella and Phascolarctobacterium both in internal and external validation cohorts. Interpretation: We provide evidence showing that intestinal bacteria profiling from baseline faecal samples can be effectively used in the clinic to improve the pre-radiotherapy assessment of gastrointestinal toxicity risk in prostate cancer patients. Funding: Italian Ministry of Health (Promotion of Institutional Research INT-year 2016, 5 × 1000, Ricerca Corrente funds). Fondazione Regionale per la Ricerca Biomedica (ID 2721017). AIRC (IG 21479).

In this data article, we present a dataset containing match scores from major international competitions for 12 popular team ball sports: basketball, cricket, field hockey, futsal, handball, ice hockey, lacrosse, roller hockey, rugby, soccer, volleyball, and water polo. The dataset was obtained by web scraping data available on Wikipedia pages and includes the following information related to individual matches: the year of the competition edition when a match occurred, the names of the two opposing teams, their respective scores, and the name of the winning team. Our match score dataset provides researchers in the field of sports analytics with valuable data that can be used to compute team statistics, develop team ranking and rating systems, infer patterns and trends in a team's performance across the edition years, build predictive models to forecast the outcome of future matches, and evaluate the performance of machine learning algorithms.

Background: Pulmonary embolism (PE) is a potentially life-threatening condition. Admission and treatment in the intensive care unit (ICU) is an important element in critically ill PE patients. Objectives: We aimed to identify risk factors for ICU admission and differences in patient profiles regarding risk factors and comorbidities between PE patients who had to be admitted to an ICU and those who were treated in a normal ward without ICU. Methods: We used the German nationwide inpatient sample to analyze all hospitalizations of PE patients in Germany from 2016 to 2020 stratified for ICU admission. Results: Overall, 484,859 hospitalized PE patients were treated in German hospitals from 2016 to 2020. Among these, 92,313 (19.0%) were admitted to ICU. Patients treated in ICU were younger (69.0 [IQR, 58.0-78.0] vs 72.0 [IQR, 60.0-80.0] years; P < .001) and had higher prevalence of cardiovascular risk factors and comorbidities. In-hospital case fatality rate was elevated in PE patients treated in ICU (22.7% vs 10.7%; P < .001), and ICU admission was independently associated with increased in-hospital case fatality (odds ratio [OR], 2.54; 95% CI, 2.49-2.59; P < .001). Independent risk factors for ICU admission comprised PE with imminent or present decompensation (OR, 3.30; 95% CI, 3.25-3.35; P < .001), hemodynamic instability (OR, 4.49; 95% CI, 4.39-4.59; P < .001), arterial hypertension (OR, 1.20; 95% CI, 1.18-1.22; P < .001), diabetes mellitus (OR, 1.16; 95% CI, 1.14-1.18; P < .001), obesity (OR, 1.300; 95% CI, 1.27-1.33; P < .001), surgery (OR, 2.55; 95% CI, 2.50-2.59; P < .001), stroke (OR, 2.86; 95% CI, 2.76-2.96; P < .001), pregnancy (OR, 1.45; 95% CI, 1.21-1.74; P < .001), heart failure (OR, 1.74; 95% CI, 1.71-1.77; P < .001), atrial fibrillation/flutter (OR, 1.69; 95% CI, 1.66-1.73; P < .001), chronic obstructive pulmonary disease (OR, 1.21; 95% CI, 1.18-1.24; P < .001), and renal failure (OR, 1.92; 95% CI, 1.88-1.95; P < .001). Conclusion: ICU treatment is an important element in the treatment of PE patients. Besides hemodynamic compromise, cardiovascular risk factors, stroke, pregnancy, and cardiopulmonary as well as renal comorbidities were independent predictors of ICU admission. Necessity of ICU admission was afflicted by increased case fatality.

Background & Aims: Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed. Methods: Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events. Results: In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1–157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7–174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977–0.995; p = 0.002). Conclusions: Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors. Impact and implications: Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

Background: Reconstruction of mandibular bone defects is a surgical challenge, and microvascular reconstruction is the current gold standard. The field of tissue bioengineering has been providing an increasing number of alternative strategies for bone reconstruction.Methods: In this preclinical study, the performance of two bioengineered scaffolds, a hydrogel made of polyethylene glycol-chitosan (HyCh) and a hybrid core-shell combination of poly (L-lactic acid)/poly (ε-caprolactone) and HyCh (PLA-PCL-HyCh), seeded with different concentrations of human mesenchymal stromal cells (hMSCs), has been explored in non-critical size mandibular defects in a rabbit model. The bone regenerative properties of the bioengineered scaffolds were analyzed by in vivo radiological examinations and ex vivo radiological, histomorphological, and immunohistochemical analyses.Results: The relative density increase (RDI) was significantly more pronounced in defects where a scaffold was placed, particularly if seeded with hMSCs. The immunohistochemical profile showed significantly higher expression of both VEGF-A and osteopontin in defects reconstructed with scaffolds. Native microarchitectural characteristics were not demonstrated in any experimental group.Conclusion: Herein, we demonstrate that bone regeneration can be boosted by scaffold- and seeded scaffold-reconstruction, achieving, respectively, 50% and 70% restoration of presurgical bone density in 120 days, compared to 40% restoration seen in spontaneous regeneration. Although optimization of the regenerative performance is needed, these results will help to establish a baseline reference for future experiments.

Summary: Dendritic cell (DC) progenitors adapt their transcriptional program during development, generating different subsets. How chromatin modifications modulate these processes is unclear. Here, we investigate the impact of histone deacetylation on DCs by genetically deleting histone deacetylase 1 (HDAC1) or HDAC2 in hematopoietic progenitors and CD11c-expressing cells. While HDAC2 is not critical for DC development, HDAC1 deletion impairs pro-pDC and mature pDC generation and affects ESAM+cDC2 differentiation from tDCs and pre-cDC2s, whereas cDC1s are unchanged. HDAC1 knockdown in human hematopoietic cells also impairs cDC2 development, highlighting its crucial role across species. Multi-omics analyses reveal that HDAC1 controls expression, chromatin accessibility, and histone acetylation of the transcription factors IRF4, IRF8, and SPIB required for efficient development of cDC2 subsets. Without HDAC1, DCs switch immunologically, enhancing tumor surveillance through increased cDC1 maturation and interleukin-12 production, driving T helper 1-mediated immunity and CD8+ T cell recruitment. Our study reveals the importance of histone acetylation in DC development and anti-tumor immunity, suggesting DC-targeted therapeutic strategies for immuno-oncology.

Diffusion-weighted Imaging (DWI) is an effective and state-of-the-art neuroimaging method that non-invasively reveals the microstructure and connectivity of tissues. Recently, novel applications of the DWI technique in studying large brains through ex-vivo imaging enabled researchers to gain insights into the complex neural architecture in different species such as those of Perissodactyla (e.g., horses and rhinos), Artiodactyla (e.g., bovids, swines, and cetaceans), and Carnivora (e.g., felids, canids, and pinnipeds). Classical in-vivo tract-tracing methods are usually considered unsuitable for ethical and practical reasons, in large animals or protected species. Ex-vivo DWI-based tractography offers the chance to examine the microstructure and connectivity of formalin-fixed tissues with scan times and precision that is not feasible in-vivo. This paper explores DWI’s application to ex-vivo brains of large animals, highlighting the unique insights it offers into the structure of sometimes phylogenetically different neural networks, the connectivity of white matter tracts, and comparative evolutionary adaptations. Here, we also summarize the challenges, concerns, and perspectives of ex-vivo DWI that will shape the future of the field in large brains.

Purpose: The purpose of this study is to study the evolution of quality of life (QoL) in the first 5 years following Intensity-modulated radiation therapy (IMRT) for prostate cancer (PCa) and to determine possible associations with clinical/treatment data. Material and methods: Patients were enrolled in a prospective multicentre observational trial in 2010-2014 and treated with conventional (74–80 Gy, 1.8–2 Gy/fr) or moderately hypofractionated IMRT (65–75.2 Gy, 2.2–2.7 Gy/fr). QoL was evaluated by means of EORTC QLQ-C30 at baseline, at radiation therapy (RT) end, and every 6 months up to 5 years after IMRT end. Fourteen QoL dimensions were investigated separately. The longitudinal evaluation of QoL was analysed by means of Analysis of variances (ANOVA) for multiple measures. Results: A total of 391 patients with complete sets of questionnaires across 5 years were available. The longitudinal analysis showed a trend toward the significant worsening of QoL at RT end for global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. QoL worsening was recovered within 6 months from RT end, with the only exception being physical functioning. Based on ANOVA, the most impaired time point was RT end. QoL dimension analysis at this time indicated that acute Grade ≥ 2 gastrointestinal (GI) toxicity significantly impacted global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. Acute Grade ≥ 2 genitourinary (GU) toxicity resulted in lower role functioning and higher pain. Prophylactic lymph-nodal irradiation (WPRT) resulted in significantly lower QoL for global health, fatigue, appetite loss, and diarrhoea; lower pain with the use of neoadjuvant/concomitant hormonal therapy; and lower fatigue with the use of an anti-androgen. Conclusions: In this prospective, longitudinal, observational study, high radiation IMRT doses delivered for PCa led to a temporary worsening of QoL, which tended to be completely resolved at six months. Such transient worsening was mostly associated with acute GI/GU toxicity, WPRT, and higher prescription doses.