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Abstract Introduction The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65 years old. Methods This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP. Results Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p

Healthy human skin tissue is often used as a control for comparison to diseased skin in patients with skin pathologies, including skin cancers or other inflammatory conditions such as atopic dermatitis or psoriasis. Although non-affected skin from these patients is a more appropriate choice for comparison, there is a paucity of studies examining such tissue. This lack is exacerbated by the difficulty of processing skin tissue for experimental analysis. In addition, choosing a processing protocol for skin tissue which preserves cell viability and identity while sufficiently dissociating cells for single-cell analysis is not a trivial task. Here, we compare three digestion methods for human skin tissue, evaluating the cell yield and viability for each protocol. We find that the use of a sequential dissociation method with multiple enzymatic digestion steps produces the highest cell viability. Using single-cell sequencing, we show this method results in a relative increase in the proportion of non-antigen-presenting mast cells and CD8 T cells as well as a relative decrease in the proportion of antigen-presenting mast cells and KYNU+ CD4 T cells. Overall, our findings support the use of this sequential digestion method on freshly processed human skin samples for optimal cell yield and viability.

Ageing is a major risk factor for cancer metastasis but the underlying mechanisms remain unclear. Here, we characterised ageing effects on cancer-induced endothelial-mesenchymal transition (EndMT) in the pulmonary circulation of female BALB/c mice in a metastatic 4T1 breast cancer model. The effect of intravenously injected 4T1 cells on pulmonary endothelium, pulmonary metastasis, lung tissue architecture, and systemic endothelium was compared between 40-week-old and 20-week-old mice. The 40-week-old mice showed features of ongoing EndMT in their lungs before 4T1 breast cancer cell injection. Moreover, they had preexisting endothelial dysfunction in the aorta detected by in vivo magnetic resonance imaging (MRI) compared to 20-week-old mice. The injection of 4T1 breast cancer cells into 40-week-old mice resulted in rapid EndMT progression in their lungs. In contrast, injection of 4T1 breast cancer cells into 20-week-old mice resulted in initiation and less pronounced EndMT progression. Although the number of metastases did not differ significantly between 20-week-old and 40-week-old mice, the lungs of older mice displayed altered lung tissue architecture and biochemical content, reflected in higher Amide II/Amide I ratio, higher fibronectin levels, and hypoxia-inducible factor 1 subunit alpha (HIF1α) levels as well as lower nitric oxide (NO) production. Our results indicate that age-dependent pre-existing endothelial dysfunction in the pulmonary endothelium of 40-week-old mice predisposed them to rapid EndMT progression in the presence of circulating 4T1 breast cancer cells what might contribute to a more severe metastatic breast cancer phenotype in these ageing mice compared to younger mice.

Abstract Endothelial dysfunction is one of the hallmarks of vascular abnormalities in metabolic diseases and has been repeatedly demonstrated in coronary and peripheral circulation in mice fed high-fat diet (HFD), particularly after long-term HFD. However, the temporal relationship between development of coronary microvascular endothelial dysfunction and deterioration in diastolic and systolic cardiac function after short-term feeding with HFD has not yet been studied. This study aimed to correlate the changes in coronary microvascular endothelial function and global cardiac performance indices in vivo after short-term feeding with HFD in mice. Short-term feeding with a HFD (60% fat + 1% cholesterol) resulted in severely impaired coronary microvascular function, as evidenced by the diminished effect of nitric oxide synthase inhibition (by L-NAME) assessed using T1 mapping via in vivo MRI. Deterioration of coronary microvascular function was detected as early as after 7 days of HFD and further declined after 8 weeks on a HFD. HFD-induced coronary microvascular dysfunction was not associated with impaired myocardial capillary density and was present before systemic insulin resistance assessed by a glucose tolerance test. Basal coronary flow and coronary reserve, as assessed using the A2A adenosine receptor agonist regadenoson, were also not altered in HFD-fed mice. Histological analysis did not reveal cardiomyocyte hypertrophy or fibrosis. Increased lipid accumulation in cardiomyocytes was detected as early as after 7 days of HFD and remained at a similar level at 8 weeks on a HFD. Multiparametric cardiac MRI revealed a reduction in systolic heart function, including decreased ejection rate, increased end-systolic volume and decreased myocardial strain in diastole with impaired ejection fraction, but not until 4 weeks of HFD. Short-term feeding with HFD resulted in early endothelial dysfunction in coronary microcirculation that preceded alteration in cardiac function and systemic insulin resistance.

Background Long‐term feeding with a high‐fat diet (HFD) induces endothelial dysfunction in mice, but early HFD‐induced effects on endothelium have not been well characterized. Methods and Results Using an magnetic resonance imaging‐based methodology that allows characterization of endothelial function in vivo, we demonstrated that short‐term (2 weeks) feeding with a HFD to C57BL/6 mice or to E3L.CETP mice resulted in the impairment of acetylcholine‐induced response in the abdominal aorta (AA), whereas, in the thoracic aorta (TA), the acetylcholine‐induced response was largely preserved. Similarly, HFD resulted in arterial stiffness in the AA, but not in the TA. The difference in HFD‐induced response was ascribed to distinct characteristics of perivascular adipose tissue in the TA and AA, related to brown‐ and white‐like adipose tissue, respectively, as assessed by histology, immunohistochemistry, and Raman spectroscopy. In contrast, short‐term HFD‐induced endothelial dysfunction could not be linked to systemic insulin resistance, changes in plasma concentration of nitrite, or concentration of biomarkers of glycocalyx disruption (syndecan‐1 and endocan), endothelial inflammation (soluble form of vascular cell adhesion molecule 1, soluble form of intercellular adhesion molecule 1 and soluble form of E‐selectin), endothelial permeability (soluble form of fms‐like tyrosine kinase 1 and angiopoietin 2), and hemostasis (tissue plasminogen activator and plasminogen activator inhibitor 1). Conclusions Short‐term feeding with a HFD induces endothelial dysfunction in the AA but not in the TA, which could be ascribed to a differential response of perivascular adipose tissue to a HFD in the AA versus TA. Importantly, early endothelial dysfunction in the AA is not linked to elevation of classical systemic biomarkers of endothelial dysfunction.

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.

Abstract Physical activity is emerging as an alternative nonpharmaceutical strategy to prevent and treat a variety of cardiovascular diseases due to its cardiac and skeletal muscle beneficial effects. Oxidative stress occurs in skeletal muscle of chronic heart failure (CHF) patients with possible impact on muscle function decline. We determined the effect of voluntary‐free wheel running (VFWR) in preventing protein damage in Tgαq*44 transgenic mice (Tg) characterized by a delayed CHF progression. In the early (6 months) and transition (12 months) phase of CHF, VFWR increased the daily mean distance covered by Tg mice eliminating the difference between Tg and WT present before exercise at 12 months of age (WT Pre‐EX 3.62 ± 1.66 vs. Tg Pre‐EX 1.51 ± 1.09 km, P 0.005). This effect was concomitant with an improvement of in vivo cardiac performance [(Cardiac Index (mL/min/cm2): 6 months, untrained‐Tg 0.167 ± 0.005 vs. trained‐Tg 0.21 ± 0.003, P 0.05). Prolonged voluntary physical activity performed before the onset of CHF end‐stage, appears to be a useful tool to increase cardiac function and to reduce skeletal muscle oxidative damage counteracting physical activity decline.

Background The impairment of endothelium‐dependent vasodilation, increased endothelial permeability, and glycocalyx degradation are all important pathophysiological components of endothelial dysfunction. However, it is still not clear whether in atherosclerosis, glycocalyx injury precedes other features of endothelial dysfunction or these events coincide. Methods and Results Herein, we demonstrate that in 4‐ to 8‐week‐old apolipoprotein E/low‐density lipoprotein receptor‐deficient mice, at the stage before development of atherosclerotic plaques, impaired acetylcholine‐induced vasodilation, reduced NO production in aorta, and increased endothelial permeability were all observed; however, flow‐mediated dilation in the femoral artery was fully preserved. In 4‐week‐old mice, glycocalyx coverage was reduced and endothelial stiffness was increased, whereas glycocalyx length was significantly decreased at 8 weeks of age. Early changes in endothelial function were also featured by increased plasma concentration of biomarkers of glycocalyx disruption (endocan), biomarkers of endothelial inflammation (soluble vascular cell adhesion molecule 1), increased vascular permeability (angiopoietin 2), and alterations in hemostasis (tissue plasminogen activator and plasminogen activator inhibitor 1). In 28‐week‐old mice, at the stage of advanced atherosclerotic plaque development, impaired NO production and nearly all other features of endothelial dysfunction were changed to a similar extent, compared with the preatherosclerotic plaque phase. The exceptions were the occurrence of acetylcholine‐induced vasoconstriction in the aorta and brachiocephalic artery, impaired flow‐mediated vasodilation in the femoral artery, and further reduction of glycocalyx length and coverage with a concomitant further increase in endothelial permeability. Conclusions In conclusion, even at the early stage before the development of atherosclerotic plaques, endothelial dysfunction is a complex multifactorial response that has not been previously appreciated.

Hyperglycemia linked to diabetes results in endothelial dysfunction. In the present work, we comprehensively characterized effects of short-term hyperglycemia induced by administration of an insulin receptor antagonist, the S961 peptide, on endothelium and perivascular adipose tissue (PVAT) in mice. Endothelial function of the thoracic and abdominal aorta in 12-week-old male C57Bl/6Jrj mice treated for two weeks with S961 infusion via osmotic pumps was assessed in vivo using magnetic resonance imaging and ex vivo by detection of nitric oxide (NO) production using electron paramagnetic resonance spectroscopy. Additional methods were used to analyze PVAT, aortic segments and endothelial-specific plasma biomarkers. Systemic disruption of insulin signaling resulted in severe impairment of NO-dependent endothelial function and a loss of vasoprotective function of PVAT affecting the thoracic as well as abdominal parts of the aorta, however a fall in adiponectin expression and decreased uncoupling protein 1-positive area were more pronounced in the thoracic aorta. Results suggest that dysfunctional PVAT contributes to vascular pathology induced by altered insulin signaling in diabetes, in the absence of fat overload and obesity.

The role of epithelial sodium channel (ENaC) activity in the regulation of endothelial function is not clear. Here, we analyze the role of ENaC in the regulation of endothelium-dependent vasodilation and endothelial permeability in vivo in mice with conditional αENaC subunit gene inactivation in the endothelium (endo-αENaCKO mice) using unique MRI-based analysis of acetylcholine-, flow-mediated dilation and vascular permeability. Mice were challenged or not with lipopolysaccharide (LPS, from Salmonella typhosa, 10 mg/kg, i.p.). In addition, changes in vascular permeability in ex vivo organs were analyzed by Evans Blue assay, while changes in vascular permeability in perfused mesenteric artery were determined by a FITC-dextran-based assay. In basal conditions, Ach-induced response was completely lost, flow-induced vasodilation was inhibited approximately by half but endothelial permeability was not changed in endo-αENaCKO vs. control mice. In LPS-treated mice, both Ach- and flow-induced vasodilation was more severely impaired in endo-αENaCKO vs. control mice. There was also a dramatic increase in permeability in lungs, brain and isolated vessels as evidenced by in vivo and ex vivo analysis in endotoxemic endo-αENaCKO vs. control mice. The impaired endothelial function in endotoxemia in endo-αENaCKO was associated with a decrease of lectin and CD31 endothelial staining in the lung as compared with control mice. In conclusion, the activity of endothelial ENaC in vivo contributes to endothelial-dependent vasodilation in the physiological conditions and the preservation of endothelial barrier integrity in endotoxemia.

Abstract Background [18F] Fluorodeoxyglucose (FDG) PET-CT is a clinical imaging modality widely used in diagnosing and staging lung cancer. The clinical findings of PET-CT studies are contained within free text reports, which can currently only be categorised by experts manually reading them. Pre-trained transformer-based language models (PLMs) have shown success in extracting complex linguistic features from text. Accordingly, we developed a multi-task ‘TNMu’ classifier to classify the presence/absence of tumour, node, metastasis (‘TNM’) findings (as defined by The Eight Edition of TNM Staging for Lung Cancer). This is combined with an uncertainty classification task (‘u’) to account for studies with ambiguous TNM status. Methods 2498 reports were annotated by a nuclear medicine physician and split into train, validation, and test datasets. For additional evaluation an external dataset (n = 461 reports) was created, and annotated by two nuclear medicine physicians with agreement reached on all examples. We trained and evaluated eleven publicly available PLMs to determine which is most effective for PET-CT reports, and compared multi-task, single task and traditional machine learning approaches. Results We find that a multi-task approach with GatorTron as PLM achieves the best performance, with an overall accuracy (all four tasks correct) of 84% and a Hamming loss of 0.05 on the internal test dataset, and 79% and 0.07 on the external test dataset. Performance on the individual TNM tasks approached expert performance with macro average F1 scores of 0.91, 0.95 and 0.90 respectively on external data. For uncertainty an F1 of 0.77 is achieved. Conclusions Our ‘TNMu’ classifier successfully extracts TNM staging information from internal and external PET-CT reports. We concluded that multi-task approaches result in the best performance, and better computational efficiency over single task PLM approaches. We believe these models can improve PET-CT services by assisting in auditing, creating research cohorts, and developing decision support systems. Our approach to handling uncertainty represents a novel first step but has room for further refinement.

Abstract The eukaryotic nucleus exhibits a highly organized 3D genome architecture, with RNA transcription and processing confined to specific nuclear structures. While intra-chromosomal interactions, such as promoter-enhancer dynamics, are well-studied, the role of inter-chromosomal interactions remains poorly understood. Investigating these interactions in mammalian cells is challenging due to large genome sizes and the need for deep sequencing. Additionally, transcription-dependent 3D topologies in mixed cell populations further complicate analyses. To address these challenges, we used high-resolution DNA-DNA contact mapping (Micro-C) in Trypanosoma brucei, a parasite with continuous RNA polymerase II (RNAPII) transcription and polycistronic transcription units (PTUs). With approximately 300 transcription start sites (TSSs), this genome organization simplifies data interpretation. To minimize scaffolding artifacts, we also generated a highly contiguous phased genome assembly using ultra-long sequencing reads. Our Micro-C analysis revealed an intricate 3D genome organization. While the T. brucei genome displays features resembling chromosome territories, its chromosomes are arranged around polymerase-specific transcription hubs. RNAPI-transcribed genes cluster, as expected from their localization to the nucleolus. However, we also found that RNAPII TSSs form distinct inter-chromosomal transcription hubs with other RNAPII TSSs. These findings highlight the evolutionary significance of inter-chromosomal transcription hubs and provide new insights into genome organization in T. brucei.

Until the late 19th century, the sources of the Hebrew Bible as well as the writings of classical Greco-Roman authors, provided the only information about the history of ancient Mesopotamia, Canaan, and other civilizations of the ancient Near East. It is difficult to determine how much Hebrew ophthalmology depends on the ophthalmology of other nations. It can only be said that the Babylonians and Egyptians had the greatest influence on it. The Jewish ancestor Abraham immigrated from Mesopotamia to Canaan, and Babylonia already had a high culture in the fourth millennium BC, also in relation to medicine in general, and ophthalmology in particular.

Abstract Tree-microbe interactions are essential for forest ecosystem functioning. Most plant–microbe research has focused on the rhizosphere, while composition of microbial communities in the phyllosphere remains underexplored. Here, we use 16S rRNA gene sequencing to explore differences between beech and Scots pine phyllospheric microbiomes at the European continental scale, map their functional profiles, and elucidate the role of host trees, forest features, and environmental factors such as climate and atmospheric deposition in phyllosphere microbiota assembly. We identified tree species and the associated foliar trait (specifically carbon:nitrogen ratio) as primary drivers of the bacterial communities. We characterized taxonomical and functional composition of epiphytic bacteria in the phyllosphere of beech and Scots pine across an environmental gradient from Fennoscandia to the Mediterranean area, with major changes in temperature and nitrogen deposition. We also showed that temperature and nitrogen deposition played a crucial role in affecting their assembly for both tree species. This study contributes to advancing our understanding on factors shaping phyllosphere microbial communities in beech and Scots pine at the European continental scale, highlighting the need of broad-scale comparative studies (covering a wide range of foliar traits and environmental conditions) to elucidate how phyllosphere microbiota mediates ecosystem responses to global change.

When and why earthquakes trigger volcano and geyser eruptions remains unclear. In September 2022, Steamboat Geyser in Yellowstone, USA erupted 8.25 hours after a local M3.9 earthquake—an improbable coincidence based on the geyser’s eruption intervals. We leverage monitoring data from the surrounding geyser basin to determine if the earthquake triggered this eruption. We calculate a peak ground velocity of 1.2 cm s−1, which is the largest ground motion in the area since Steamboat reactivated in March 2018 and exceeds a threshold associated with past earthquake-triggered geyser eruptions in Yellowstone. Despite no changes in other surface hydrothermal activity, we found abrupt, short-lived shifts in ambient seismic noise amplitude and relative seismic velocity in narrow frequency bands related to the subsurface hydrothermal system. Our analysis indicates that Steamboat’s eruption was likely earthquake-triggered. The hours-long delay suggests that dynamic strains from seismic waves altered subsurface permeability and flow which enabled eruption.

The Common Core Standards for Mathematical Practice describe mathematical habits of mind foundational for mathematical thinking and understanding. The Statistical Education of Teachers (SET) report, commissioned by the American Statistical Association (ASA), interprets the Mathematical Practices through a statistical lens. In this article, we present tasks focused on variability that can be taught through the lens of Mathematical Practice 6: Attending to Precision (MP6). We show that teacher tasks that focus on variability and its quantification (by computing multiple different measures on different aspects of an entire dataset and constructing arguments), prompts teachers to attend to statistical precision. Additionally, we make the connection that ideas related to variability are present in all components of the statistical investigative process: posing questions that anticipate variability, anticipating variability in data collection, analyzing the variability present, and interpreting the variability to make quantitative statements about error and tasks that aim toward understanding variability require the employment of Statistical MP6.

Abstract Three-finger proteins are the most abundant toxins in the venom of Naja ashei, a snake species from the Elapidae family. This research aimed to describe the effects of varying charges of these proteins, isolated from Naja ashei venom using SEC and IEX chromatography. The study examined how differently charged three-finger toxin fractions interact with and affect neuroblastoma (SK-N-SH) and promyeloblast (HL-60) cells, as well as model Langmuir membranes and liposomes designed to mimic cellular lipid composition. Findings revealed that protein surface charges significantly impact cell survival (MTT assay), membrane damage (lactate dehydrogenase release, malondialdehyde formation), and the structural and electrochemical properties of model membranes (Langmuir membranes and zeta potential for liposomes and cancer cell lines). Results indicated that SK-N-SH cells, characterized by a higher negative charge on their cell membranes, interacted more effectively with positively charged toxins than HL-60 cells. However, the mechanism of these electrostatic interactions is complex. The research demonstrated that electrostatic and mechanical membrane modifications induced by venom proteins can significantly affect cell metabolism. Additionally, the total charge of the membrane, influenced by polar lipid components and phospholipid saturation, plays a decisive role in toxin interaction.

Abstract Background This study aims to examine risk of adverse pregnancy outcomes and mothers’ characteristics in patients with chronic hypertension, gestational hypertension and preeclampsia. Methods The study included all births born from women aged 15–45 years, in Lleida, Spain from 2012 to 2018. Pregnancy outcomes were retrieved by regional administrative databases. Logistic regression analysis was used to calculate adjusted odds ratios (OR) (OR 95% CI) for maternal characteristics or neonatal outcomes. Results Among 17,177 pregnant women, different types of hypertension present varying risks for both the mother and fetus. There is an increased risk of cesarean section in patients with preeclampsia (OR 2.04, 95% CI: 1.43–2.88). For the newborn, a higher risk of preterm birth is associated with maternal chronic hypertension (OR 3.09, 95% CI: 1.91–4.83) and preeclampsia (OR 5.07, 95% CI: 3.28–7.65). Additionally, there is a higher risk of low birth weight in cases of maternal chronic hypertension (OR 3.2, 95% CI: 2.04–4.88), preeclampsia (OR 5.07, 95% CI: 3.34–7.52), and gestational hypertension (OR 2.72, 95% CI: 1.49–4.68). Furthermore, only newborns of patients with preeclampsia had a higher risk of an Apgar score lower than 7 in the first minute (OR 2.95, 95% CI: 1.45–5.38). Conclusions In the study population adjusted for body weight, the different types of hypertension represent different risks in the mother and foetus. These complications were mostly associated with preeclampsia.

Summary: Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, deadly lung disease with several factors, including respiratory tract infections (RTI), for disease worsening. There's no comprehensive data on RTI incidence in IPF patients across different therapies, including antifibrotic (nintedanib or pirfenidone), investigative or placebo treatments. Methods: A systematic search of databases Medline, EMBASE, Cochrane Central, Web of Science and Scopus was conducted on September 30th 2024 (PROSPERO registration number: CRD42023484213). Only randomized controlled trials of drugs intended for IPF treatment in adults and reporting RTI incidence were included. Pooled risk ratio with 95% confidence interval (CI), risk of bias, GRADE and CINEMA assessments were conducted along with subgroup analyses for upper and lower RTI and for different antifibrotic doses. Findings: A total of 27 trials of different drugs aimed for IPF therapy were pooled in a pairwise meta-analysis, 11,542 patients were analyzed with an overall number of 4156 RTI events, representing an average incidence of 38.4 ± 23.5%. Most therapies did not affect RTI risk in IPF, although single trials with everolimus and trimethoprim/sulfamethoxazole showed a significant decrease compared to placebo. For antifibrotics, RTI incidence was similar with pirfenidone treatment compared to nintedanib (RR: 0.98 CI: [0.71; 1.36]) and compared to placebo (RR: 0.88 CI: [0.69; 1.10]) and nintedanib compared to placebo (RR: 0.89 CI: [0.71; 1.12]). Interpretation: RTIs are frequently reported adverse events in IPF patients over a one-year period, with different investigated treatments showing no profound impact compared to placebo. Future clinical trials should focus on targeting treatable traits like RTIs. Funding: None.

Resumo Neste artigo refletimos sobre o trabalho remunerado nos domicílios brasileiros. Procuraremos observar a diversidade das suas configurações, seja pelo prisma da literatura acadêmica, seja à luz de dados mais recentes, que nos permitem dimensioná-lo. Assim, mostraremos como serviços domésticos e de cuidado figuram na literatura ora de maneira fragmentada, como campos distintos, ora de maneira articulada, subsumidos em um campo mais amplo, obrigando a encarar dilemas analíticos desafiadores. Evidenciaremos, também, como os recentes movimentos do mercado de trabalho não apenas estimulam novos enquadramentos teóricos, como deixam pistas para entender a produção e diluição das fronteiras entre tais ocupações, iluminando os dilemas identitários que se colocam.

The increasing availability of spaceborne hyperspectral satellite imagery opens new opportunities for forest habitat mapping and monitoring, but the limitation of its generally low temporal resolution must be considered. In this study, we compare the ability of single-date PRISMA (PRecursore IperSpettrale della Missione Applicativa), the hyperspectral satellite from the Italian Space Agency, with that of both single-date and multi-date Sentinel-2 (S2) and PlanetScope (PS) to detect and correctly classify various EUNIS habitat types distributed over a relatively small spatial extent (6000 ha) in a natural reserve in Central Italy. The case study deals with multiple levels of spectral similarity, as the dominant canopy species of the target forest habitat classes belong to the same genus (Quercus spp., both deciduous and evergreen species) as well as of different taxa (Pinus and Fraxinus spp.). We performed a pixel-based classification with the Random Forest algorithm using a set of 22 spectral indices computed on S2, and 12 on PS, and compared the results with those obtained by PRISMA (28 indices). A Canopy Height Model (CHM) was also used as an input variable for the classification. The single date classification of PlanetScope obtained lower overall accuracy (69 %) than what obtained with other sensors (PRISMA and Sentinel-2) in a previous study over the same area. Regarding the comparison between multi-date multispectral and single-date hyperspectral, 10-fold cross-validation results revealed that S2 achieves an out-of-bag error rate of approximately 16 %, and PS 19 %, while PRISMA result from previous study achieves 17 %. This demonstrates that a combination of spectral indices calculated during the growing season can capture phenological or physiological differences among the target species, which consequently results in a significant improvement in the classification accuracy of the multispectral sensors. Ultimately, classification results from all three sensors were combined to create probability maps for each forest class, identifying areas classified with a higher degree of certainty by each satellite tested and potentially contributing to forest management by defining areas with varying conservation levels.

The therapeutic capabilities of autologous stem cells can be fully exploited if their survival after implantation is improved.For the first time, we compared three hydrogels, with different chemical structure, morphology, and viscoelastic properties, where the same differentiation factors were immobilized and spheroids from adipose stem cells (SASCs) were incorporated. The aim is to understand if hydrogel characteristics could influence the viability of the embedded stem cells. Specifically, hydrogels of partially degalactosylated xyloglucan (dXG), sodium alginate (Alg) and k-carrageenan (kC) were produced. The structure of the networks was probed by swelling/erosion measurements, rheological and morphological analysis. Cell viability was measured after 7 and 21 days. When SASCs were incubated under stemness conditions, dXG and kC hydrogels provide the optimal environment for cell viability. When incubated in the chondrogenic or osteogenic medium, a clear correlation was found between the storage and loss moduli and cell viability. Hydrogels with the lowest shear stiffness promote stem-cell differentiation and proliferation. The systems, particularly dXG, seem more similar to natural ECM and able to recreate niches, that colonized with stem cells could represent a real support in regenerative therapies. The injectability of formulations was evaluated to determine if they could be used for minimally invasive regenerative medicine interventions.

Introduction and aim Diabetes is a global health emergency with increasing prevalence and diabetes-associated morbidity and mortality. One of the challenges in optimising diabetes care is translating research advances in this heterogeneous disease into clinical care. A potential solution is the introduction of precision medicine approaches into diabetes care.We aim to develop a digital platform called ‘intelligent Diabetes’ (iDiabetes) to support a precision diabetes care model in Scotland and assess its impact on the primary composite outcome of all-cause mortality, hospitalisation rate, renal function decline and glycaemic control.Methods and analysis The impact of iDiabetes will be evaluated through a cluster-randomised controlled study, recruiting up to 22 500 patients with diabetes. Primary care general practices (GPs) in the National Health Service (NHS) Scotland Tayside Health Board are the units (clusters) of randomisation. Each primary care GP will form one cluster (approximately 400 patients per cluster), with up to 60 clusters recruited. Randomisation will be to iDiabetes (guideline support), iDiabetesPlus or usual diabetes care (control arm). Patients of participating primary care GPs are automatically enrolled on the study when they attend for their annual diabetes screening or are newly diagnosed with diabetes. A composite hierarchical primary outcome, evaluated using Win-Ratio statistical methodology, will consist of (1) all-cause mortality, (2) all-cause hospitalisation rate, (3) proportion with >40% estimated glomerular filtration rate [eGFR] reduction from baseline or new development of end-stage renal disease, (4) proportion with absolute HbA1C reduction >0.5%. Outcomes will be evaluated after a 2-year median follow-up period. Comprehensive qualitative and health economic analyses will be conducted, assessing the cost-effectiveness, budget impact and user acceptability of the iDiabetes platform.Ethics and dissemination This study was reviewed by the NHS Health Research Authority and approved by the East of Scotland Research Ethics Committee (reference: 23/ES/0008). Study findings will be disseminated via publications, presented at scientific conferences and shared with patients and the public on the study website and social media.Trial registration number ISRCTN18000901.

Background: HIV/AIDS remains a highly stigmatizing disease worldwide, preventing people with risk or infection from testing to learn their HIV status, accessing supportive services, or taking antiretroviral therapy. Despite many studies of HIV in blood donors, no studies have evaluated the factors that contribute to stigma surrounding this illness following notification process and counseling provided by blood centers. Methods: A cross-sectional questionnaire-based survey was conducted between 2016 and 2017. Persons with HIV were invited to return to the blood center for an audio computer-assisted interview after participation in an HIV risk factor assessment study conducted from 2007 to 2016. The questionnaire was based on HIV risk interviews developed by the US CDC, with modifications appropriate to the Brazilian setting which aimed to evaluate their follow-up activities, perceptions of HIV stigma and discrimination, and the quality of counseling and notification after the donation that tested positive for HIV. Response frequencies and adjusted odds ratios from multivariable logistic regression analyses are reported. Results: 268 HIV-positive blood donors agreed to participate in the study. Almost all participants, 262 (97 %), rated as very important or important the blood center counseling experience in their decision to seek health care. One-hundred-five (39 %) participants reported none to low levels of stigma, and 163 (61 %) participants moderate stigma. Individuals reporting heterosexual orientation (OR=2.13, 95 % CI [1.08‒4.22]) and healthcare-seeking behavior (OR=2.46, 95 % CI [1.10‒5.48]) had significantly increased odds of reporting moderate levels of stigma. Conclusions: Our study provides information about perceived stigma and discrimination in the Brazilian blood donor population and reinforces the importance of the counseling process in linkage to care and reducing HIV-related stigma.

In recent years, significant advancements have been made in utilizing nanoparticles (NPs) to modulate immune responses within the central nervous system (CNS), offering new opportunities for nanotherapeutic interventions in neurological disorders. NPs can serve as carriers for immunomodulatory agents or platforms for delivering nucleic acid-based therapeutics to regulate gene expression and modulate immune responses. Several studies have demonstrated the efficacy of NP-mediated immune modulation in preclinical models of neurological diseases, including multiple sclerosis, stroke, Alzheimer’s disease, and Parkinson’s disease. While challenges remain, advancements in NPs engineering and design have led to the development of NPs using diverse strategies to overcome these challenges. The nano-bio interface with the immune system is key in the conceptualization of NPs to efficiently act as nanotherapeutics in the CNS. The biomolecular corona plays a pivotal role in dictating NPs behavior and immune recognition within the CNS, giving researchers the opportunity to optimize NPs design and surface modifications to minimize immunogenicity and enhance biocompatibility. Here, we review how NPs interact with the CNS immune system, focusing on immunosurveillance of NPs, NP-induced immune reprogramming and the impact of the biomolecular corona on NPs behavior in CNS immune responses. The integration of NPs into CNS nanotherapeutics offers promising opportunities for addressing the complex challenges of acute and chronic neurological conditions and pathologies, also in the context of preventive and rehabilitative medicine. By harnessing the nano-bio immune interface and understanding the significance of the biomolecular corona, researchers can develop targeted, safe, and effective nanotherapeutic interventions for a wide range of CNS disorders to improve treatment and rehabilitation. These advancements have the potential to revolutionize the treatment landscape of neurological diseases, offering promising solutions for improved patient care and quality of life in the future.

Introduction While changes in the prevalence of depressive symptoms during the COVID-19 pandemic have been described across populations, few studies have incorporated multidimensional variables to characterise the varying effects of the pandemic on the population’s mental health.Methods This cohort study included 6423 participants aged ≥18 years from the Icelandic COVID-19 National Resilience Cohort. Data on depressive symptoms and pandemic-related and non-pandemic-related factors were obtained during three pandemic assessment periods (baseline, follow-up wave 1 and follow-up wave 2; April 2020–December 2021), while health outcomes were obtained during the post-pandemic assessment period (follow-up wave 3; September 2022–February 2023). We used latent growth mixture models to identify variation in depressive symptom trajectories during the pandemic. We then used XGBoost models with 37 pandemic-related and non-pandemic-related factors to characterise these trajectories. Moreover, we performed linear regression to assess the association between the identified trajectories and post-pandemic health outcomes.Results Of the included participants, we identified four depressive symptom trajectories, including consistently low (83.7%), consistently high (5.3%), initially high (5.1%) and late-onset high (5.9%) symptom trajectories. Individuals who exercised frequently (≥3 days/week) and enjoyed social and family support were more likely to experience a consistently low symptom trajectory. In contrast, individuals with a history of psychiatric disorders, women and young adults (18–39 years) were less likely to follow the consistently low symptom trajectory. Moreover, compared with the consistently low symptom trajectory, the other trajectories were associated with significantly higher levels of depressive, anxiety and somatic symptoms and cognitive problems during the post-pandemic period.Conclusions Our results underscore the long-lasting impact of the COVID-19 pandemic on population mental health. Interventions focusing on exercise, social support and family support may mitigate the adverse mental health effects of future pandemics.

Abstract In therapies, curcumin is now commonly formulated in liposomal form, administered through injections or creams. This enhances its concentration at the cellular level compared to its natural form ingestion. Due to its hydrophobic nature, curcumin is situated in the lipid part of the membrane, thereby modifying its properties and influencing processes The aim of the research was to investigate whether the toxicity of specific concentrations of curcumin, assessed through biochemical tests for the SK-N-SH and H-60 cell lines, is related to structural changes in the membranes of these cells, caused by the localization of curcumin in their hydrophobic regions. Biochemical tests were performed using spectrophotometric methods. Langmuir technique were used to evaluate the interaction of the curcumin with the studied lipids. Direct introduction of curcumin into the membranes alters their physicochemical parameters. The extent of these changes depends on the initial properties of the membrane. In the conducted research, it has been demonstrated that curcumin may exhibit toxicity to human cells. The mechanism of this toxicity is related to its localization in cell membranes, leading to their dysfunction. The sensitivity of cells to curcumin presence depends on the saturation level of their membranes; the more rigid the membrane, the lower the concentration of curcumin causes its disruption.

Quantifying volatile concentrations in magmas is critical for understanding magma storage, phase equilibria, and eruption processes. We present PyIRoGlass, an open-source Python package for quantifying concentrations of H2O and CO2 species in the transmission FTIR spectra of basaltic to andesitic glasses. We leverage a dataset of natural melt inclusions and back-arc basin basalts with volatiles below detection to delineate the fundamental shape and variability of the baseline underlying the CO32- and H2Om, 1635 peaks, in the mid-infrared region. All Beer-Lambert Law parameters are examined to quantify associated uncertainties. PyIRoGlass employs Bayesian inference and Markov Chain Monte Carlo sampling to fit all probable baselines and peaks, solving for best-fit parameters and capturing covariance to offer robust uncertainty estimates. Results from PyIRoGlass agree with independent analyses of experimental devolatilized glasses (within 6 %) and interlaboratory standards (10 % for H2O, 6 % for CO2). We determine new molar absorptivities for basalts, εH2Ot,3550 = 63.03 ± 4.47 L/mol · cm and εCO2−3,1515,1430 = 303.44 ± 9.20 L/mol · cm; we additionally update the composition-dependent parameterizations of molar absorptivities, with their uncertainties, for all H2O and CO2 species peaks. The open-source nature of PyIRoGlass ensures its adaptability and evolution as more data become available.

Abstract Exposures to social and environmental stressors arise individual behavioural response and thus indirectly affect cardiometabolic health. The aim of this study was to investigate several social and environmental stressors and the paths of their influence on cardiometabolic health. The data of 2154 participants (aged 25–64 years) from the cross-sectional population-based study were analysed. The composite score of metabolic disorders (MS score) was calculated based on 5 biomarkers: waist circumference, blood pressure, fasting blood glucose, HDL-cholesterol, triglycerides. The effects of social stressors (education level, income), environmental stressors (NO2, noise) and behavioural factors (unhealthy diet, smoking, alcohol consumption, sedentary behaviours) on MS score were assessed using a structural model. We observed a direct effect of education on MS score, as well as an indirect effect mediated via an unhealthy diet, smoking, and sedentary behaviours. We also observed a significant indirect effect of income via sedentary behaviours. The only environmental stressor predicting MS was noise, which also mediated the effect of education. In summary, the effect of social stressors on the development of cardiometabolic risk had a higher magnitude than the effect of the assessed environmental factors. Social stressors lead to an individual’s unhealthy behaviour and might predispose individuals to higher levels of environmental stressors exposures.

Purpose: The paper analyses the challenges and potential benefits that stem from the relationship between an auditing firm and the companies engaged in mandatory sustainability reporting from the companyʼs point of view. Methodology/approach: Semi-structured interviews were conducted with a sample of Polish companies that engage in mandatory non-financial disclosure. Findings: The evidence collected through the interviews suggests that cooperation with an auditing company that goes beyond the minimum normative requirements brings benefits to the reporting company while also improving the non-financial reporting process, as well as the companyʼs awareness. This is particularly true for companies that started their non-financial reporting experience when it was not mandatory, as they were able to gradually adopt and grasp the related potential benefits. Research limitations/implications: A significant limitation is that the research was conducted on a small sample. To draw broader conclusions, the sample should be expanded to include additional companies. Originality/value: The paper provides empirical evidence on the relationship and cooperation between companies and auditors in the field of non-financial reporting, focusing on the conditions that enable the potential benefits of this relationship to materialize. Such relationships can be essential drivers that foster a sustainability culture within companies.

Abstract Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is also a major risk factor for ischemic stroke. The main objective of our study was to identify direct and indirect costs of AF and AF-related stroke in Slovakia. Methods We conducted a retrospective population-based study of AF and stroke related costs both from the third-party healthcare payers and societal perspective. The prevalence and incidence of AF and stroke were determined from central government run healthcare database. Further we estimated both indirect and direct costs of AF and stroke. All costs and healthcare resources were assessed from 2015 through 2019 and were expressed in the respective year. Results Over the 5-year study period, the prevalence of AF increased by 26% to a total of 149,198 AF cases in 2019, with an estimated total annual economic burden of €66,242,359. Direct medical costs accounted for 94% of the total cost of AF. The total cost of treating patients with stroke in 2019 was estimated at €89,505,669. As a result, the medical costs of stroke that develops as a complication of AF have been estimated to be €25,734,080 in 2019. Conclusions Our study shows a substantial economic burden of AF and AF-related stroke in Slovakia. In view of the above, both screening for asymptomatic AF in high-risk populations and effective early management of AF with a focused on thromboprophylaxis rhythm control should be implemented.

The role of the hydrogels in cell differentiation and proliferation is critical to the development of tissue engineering and regenerative medicine applications. Understanding the specific mechanisms by which hydrogels interact with cells and how they might influence their behaviour could lead to the design of more effective systems. We analysed the proliferation and mRNAs expression of the spheroids from adipose stem cells (SASCs) mixed to partially degalactosylated xyloglucan (dXG) in a generic culture medium without specific stimulus to assess whether the hydrogel is an “active” or “passive” component in a regenerative context. Overall, our results showed that dXG-based niches with the lowest polymer concentration (1 %w), without recourse to biochemical induction can support cell proliferation and higher commitment toward mesenchymal differentiation.Hypothesis: Partially degalactosylated xyloglucan hydrogels function as an ''active'' component in regulating the proliferation and gene expression of adipose stem cell spheroids for regenerative applications.

Background: In recent years, the quadriceps tendon has gained popularity for primary anterior cruciate ligament (ACL) reconstruction surgery due to its robustness, easy access, and ability to be tailor-made to each patient. However, concerns remain regarding potential complications associated with quadriceps tendon harvest, including impaired healing and damage to the extensor mechanism. Indications: Preserving the quadriceps paratenon, which is a source of blood supply, nutrients, and therapeutic cells during ACL reconstruction surgery, may improve postoperative outcomes by mitigating potential adverse effects associated with quadriceps harvest. As a result, it may also facilitate the quadriceps healing process and postoperative rehabilitation. Technique Description: The incision area is marked approximately 1 cm below to 3 cm above the proximal patellar pole, and the skin is dissected from the underlying tendon, exposing both the quadriceps and its paratenon. Once the tendon insertion to the patella's proximal pole is visualized, a double-blade knife is used to make a full-thickness 2-cm longitudinal cut, taking care not to cut over 2 cm of the overlying paratenon. Then, the distal end of the tendon is safely detached from the patella followed by placing continuous whip sutures, which are then loaded on a graft harvesting system and cannula. The cannula is gently plunged underneath the paratenon while applying tension on the whip sutures with the knee flexed to 90°. Then, the cannula is twisted repeatedly under the paratenon until the desired length of 61/2 to 7 cm is reached. Again, care is taken not to lever the tendon and to harvest it along its anatomic course. Finally, the quad tendon cutter is used to transect the quad at its proximal end. During the procedure, knee extension and flexion are used to aid visualization and access to the tendon's ends. Results: Preservation of the quadriceps paratenon during its harvest for ACL reconstruction surgery can potentially improve postoperative outcomes by facilitating healing and reducing friction between the tendon and neighboring tissue. Discussion/Conclusions: Preserving the quadriceps paratenon during ACL reconstruction surgery is a technique that can be easily performed and has the potential to improve postoperative outcomes. By preserving the paratenon, surgeons can reduce potential adverse effects associated with quadriceps harvest, such as impaired healing and damage to the extensor mechanism. Based on our experience and the available literature, we believe that preserving the paratenon during quadriceps tendon harvest is a valuable technique that surgeons should consider when performing ACL reconstruction surgery. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.