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Abstract The wind energy requirements for high temporal and spatial observations, unavailable in many countries, are met by reanalysed wind data, which are increasingly used in wind power assessments. However, these data also include unrealistic features, making their validation compulsory. The validation analysis of ERA5 and MERRA-2 wind data, two of the most successful wind reanalyses, with observations near Morocco’s coast, highlighted the existence of bias in both datasets, and other shortcomings. The study was conducted at eight selected sites in the period 2011-2020 using linear and probability density function based statistical tests. The local ERA5-BA and MERRA-2 BA velocity fields were created using Bias Adjustment (BA) Techniques. Only part of the observed and modelled datasets (training period) were used to identify the transfer function. The BA fields were verified against observations during the remaining period (verification period). They outperformed their respective non-adjusted fields and also the WFDE5 (the global bias-corrected ERA5 wind field) in the wind potential assessments, represented by capacity factor and low-wind day. At every location, the relative errors in the latter’s estimates using ERA5-BA were lowered to less than 10 %, and the same was true for MERRA-2-BA. Thus, an observational dataset of reduced length can help overcome some reanalysed wind data limitations for wind power estimations. Additionally, this methodology can be applied to the correction of each reanalysis update.

Abstract PEGylation (the covalent attachment of one or more poly(ethylene glycol) (PEG) units to a therapeutic) is a well-established technique in the pharmaceutical industry to increase blood-residence time and decrease immunogenicity. A challenging aspect of PEGylation is the dispersity of PEGylation agents, which results in batch-to-batch variations and analytical limitations. Herein, we present an approach to overcome these limitations by manufacturing a defined molecular weight (dispersity-free) PEGylation agent. We synthesise a defined molecular weight (Mw), linear 5 kDa methoxy-PEG (mPEG) active ester in an efficient and scalable manner using an iterative liquid-phase approach based on Nanostar Sieving. We then perform a comparative study on the random PEGylation and subsequent characterisation of the protein bovine serum albumin (BSA), using both the defined Mw, dispersity-free mPEG active ester, and a commercially available disperse 5 kDa mPEG active ester. We demonstrate that the defined Mw PEG both allows for facile monitoring of chemical modification reactions during the synthesis of the PEGylation agents, and facilitates straightforward identification of the PEGylated fragments within a PEGylated protein via a simple peptide mapping approach using UPLC-MS.

Abstract Background Onchocerciasis and lymphatic filariasis (LF) are endemic in Equatorial Guinea with notable variations in disease incidence between island and mainland regions. Historically, efforts to control and map these diseases were concentrated in Bioko Island, where loiasis is absent, allowing for targeted onchocerciasis interruption strategies. With the cessation of onchocerciasis transmission on Bioko and no reported cases on Annobon island, assessing the transmission status in the previously unaddressed mainland region has become imperative. Mapping efforts in mainland Equatorial Guinea have proven low to moderate level of transmission for LF and onchocerciasis, although the results so far have not been very conclusive. The current study aims to update the prevalence estimates for onchocerciasis and LF in mainland Equatorial Guinea using various diagnostic techniques. Methods This is the first cross-sectional study carried out to estimate the prevalence of onchocerciasis and LF in the mainland area of Equatorial Guinea, from September to December 2019, based on the combination of skin snip biopsies, thick blood smears, laboratory serological tests (ELISA tests for the detection of IgG4 antibodies against Onchocerca volvulus recombinant antigen Ov16 and Wuchereria bancrofti recombinant antigen Wb123) and molecular laboratory tests. Frequencies and prevalence rates, along with 95% confidence intervals for interval estimation of a binomial proportion, were computed. Results The overall onchocerciasis seroprevalence calculated for the study was 0.3% (95% CI: 0.1 to 0.5%). Microscopic examination of skin biopsies from the eight individuals seropositive for Ov16, out of the 3951 individuals initially tested, revealed no O. volvulus microfilariae. However, DNA extracted from one skin snip was successfully amplified, with subsequent sequencing confirming the presence of O. volvulus. Among the 3951 individuals, 182 were found to have anti-Wb123 antibodies, suggesting exposure to W. bancrofti, with an estimated seroprevalence of 4.6% (95% CI: 4.0 to 5.3%). Microscopy and Filaria-real time-PCR (F-RT-PCR) analysis for W. bancrofti were negative across all samples. Conclusions The findings indicate that onchocerciasis may no longer constitutes a public health problem in Equatorial Guinea, positioning the country on the verge of achieving elimination. Additionally, the mapped prevalence of LF will facilitate the formulation of national strategies aimed at eradicating filariases countrywide. Graphical Abstract

This microreview, conducted by interdisciplinary teams, examines complex heritage material systems, such as medieval colors and modern and contemporary artworks. Our multi-analytical approach, a significant aspect of our research, is a means to this end. The conservation of works of art is our shared goal, as it ensures their accessibility and the transfer of cultural heritage to future generations. We seek to interpret the damage, usefulness, and innovation of the experimental design in this context. As Jan Wouters rightly points out, “The terminology used nowadays to describe the potential damage to objects caused by analysis should be refined beyond the destructiveness/non-invasiveness polarization. A terminology should include at least degree level intervention (low, medium, high), usefulness, and innovation”. Complementing micro- or sub-micro-sampling with the appropriate analytical methods is crucial, as exemplified in medieval, modern, and contemporary collections studies. Finally, a novel perspective for exploring the information contained in the multiscale heterogeneity of organic historical materials is envisaged, and it includes UV/Visible photoluminescence spectral imaging using a low-intensity ultraviolet synchrotron beam.

Abstract Aboveground biomass density (AGBD) estimates from Earth Observation (EO) can be presented with the consistency standards mandated by United Nations Framework Convention on Climate Change (UNFCCC). This article delivers AGBD estimates, in the format of Intergovernmental Panel on Climate Change (IPCC) Tier 1 values for natural forests, sourced from National Aeronautics and Space Administration’s (NASA’s) Global Ecosystem Dynamics Investigation (GEDI) and Ice, Cloud and land Elevation Satellite (ICESat-2), and European Space Agency’s (ESA’s) Climate Change Initiative (CCI). It also provides the underlying classification used by the IPCC as geospatial layers, delineating global forests by ecozones, continents and status (primary, young (≤20 years) and old secondary (>20 years)). The approaches leverage complementary strengths of various EO-derived datasets that are compiled in an open-science framework through the Multi-mission Algorithm and Analysis Platform (MAAP). This transparency and flexibility enables the adoption of any new incoming datasets in the framework in the future. The EO-based AGBD estimates are expected to be an independent contribution to the IPCC Emission Factors Database in support of UNFCCC processes, and the forest classification expected to support the generation of other policy-relevant datasets while reflecting ongoing shifts in global forests with climate change.

Abstract In seasonal environments, organisms with complex life cycles not only contend with seasonal time constraints (TC) but also increasingly face global change stressors that may interfere with responses to TC. Here, we tested how warming and predator stress imposed during the egg and larval stages shaped life history and behavioural responses to TC in the temperate damselfly Ischnura elegans. Eggs from early and late clutches in the season were subjected to ambient and 4 °C warming temperature and the presence or absence of predator cues from perch and signal crayfish. After hatching, larvae were retained at the same thermal regime, and the predator treatment was continued or not up to emergence. The late eggs decreased their development time, especially under warming and when not exposed to predator cues. However, the late eggs increased their development time when exposed to predator cues, especially to crayfish cues. The TC decreased survival of late larvae that were as eggs exposed to crayfish cues, indicating a carry-over effect. The TC and warming additively reduced late larvae development time to emergence. Independent of the TC, predator cue effects on development time were stronger during the egg than during the larval stage. The late individuals expressed lower mass at emergence, which mirrored the size difference between field-collected mothers. Warming caused a higher mass at emergence. The late individuals increased their boldness and showed a higher number of moves, whereas warming caused a decreased boldness. There was no predator cue effect on larval behaviour. The results indicate that late individuals compensate for late season egg laying, which is facilitated under warming but counteracted under predation risk, especially when imposed by the crayfish.

Abstract The duality relating the four-dimensional Kerr-Taub-NUT black hole to a thermal two-dimensional CFT with central charges c L = c R = 12J 0 is analyzed in detail, generalizing an argument given recently for Kerr within the soft-hair approach. The hidden conformal symmetry is realized in the form of V ir L × V ir R diffeomorphisms which act non-trivially on the black hole horizon. Semiclassical formulae are derived for the temperature and central charges of the dual CFT. Assuming the applicability of the Cardy formula, these CFT quantities precisely reproduce the macroscopic Bekenstein-Hawking area law. Various further generalizations including the complete family of black holes in four dimensions are discussed.

Abstract Background Nelore cattle play a key role in tropical production systems due to their resilience to harsh conditions, such as heat stress and seasonally poor nutrition. Monitoring their genetic diversity is essential to manage the negative impacts of inbreeding. Traditionally, inbreeding and inbreeding depression are assessed by pedigree-based coefficients (F), but recently, genetic markers have been preferred for their precision in capturing the inbreeding level and identifying animals at risk of reduced productive and reproductive performance. Hence, we compared the inbreeding and inbreeding depression for productive and reproductive performance traits in Nelore cattle using different inbreeding coefficient estimation methods from pedigree information (FPed), the genomic relationship matrix (FGRM), runs of homozygosity (FROH) of different lengths (> 1 Mb (genome), between 1 and 2 Mb - FROH 1−2; 2–4 Mb FROH 2−4 or > 8 Mb FROH >8) and excess homozygosity (FSNP). Results The correlation between FPed and FROH was lower when the latter was based on shorter segments (r = 0.15 with FROH 1−2, r = 0.20 with FROH 2−4 and r = 0.28 with FROH 4−8). Meanwhile, the FPed had a moderate correlation with FSNP (r = 0.47) and high correlation with FROH >8 (r = 0.58) and FROH−genome (r = 0.60). The FROH−genome was highly correlated with inbreeding based on FROH>8 (r = 0.93) and FSNP (r = 0.88). The FGRM exhibited a high correlation with FROH−genome (r = 0.55) and FROH >8 (r = 0.51) and a lower correlation with other inbreeding estimators varying from 0.30 for FROH 2−4 to 0.37 for FROH 1−2. Increased levels of inbreeding had a negative impact on the productive and reproductive performance of Nelore cattle. The unfavorable inbreeding effect on productive and reproductive traits ranged from 0.12 to 0.51 for FPed, 0.19–0.59 for FGRM, 0.21–0.58 for FROH−genome, and 0.19–0.54 for FSNP per 1% of inbreeding scaled on the percentage of the mean. When scaling the linear regression coefficients on the standard deviation, the unfavorable inbreeding effect varied from 0.43 to 1.56% for FPed, 0.49–1.97% for FGRM, 0.34–2.2% for FROH−genome, and 0.50–1.62% for FSNP per 1% of inbreeding. The impact of the homozygous segments on reproductive and performance traits varied based on the chromosomes. This shows that specific homozygous chromosome segments can be signs of positive selection due to their beneficial effects on the traits. Conclusions The low correlation observed between FPed and genomic-based inbreeding estimates suggests that the presence of animals with one unknown parent (sire or dam) in the pedigree does not account for ancient inbreeding. The ROH hotspots surround genes related to reproduction, growth, meat quality, and adaptation to environmental stress. Inbreeding depression has adverse effects on productive and reproductive traits in Nelore cattle, particularly on age at puberty in young bulls and heifer calving at 30 months, as well as on scrotal circumference and body weight when scaled on the standard deviation of the trait.

Abstract Background Epicardial adipose tissue (EAT) surrounds the heart and is hypothesised to play a role in the development of heart failure (HF). In this study, we first investigated the differences in gene expression between epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) in patients undergoing elective coronary artery bypass graft (CABG) surgery (n = 21; 95% male). Secondly, we examined the association between EAT and SAT in patients at risk for HF stage A (n = 12) and in pre-HF patients, who show signs but not symptoms of HF, stage B (n = 9). Results The study confirmed a distinct separation between EAT and SAT. In EAT 17 clusters of genes were present, of which several novel gene modules are associated with characteristics of HF. Notably, seven gene modules showed significant correlation to measures of HF, such as end diastolic left ventricular posterior wall thickness, e’mean, deceleration time and BMI. One module was particularly distinct in EAT when compared to SAT, featuring key genes such as FLT4, SEMA3A, and PTX3, which are implicated in angiogenesis, inflammation regulation, and tissue repair, suggesting a unique role in EAT linked to left ventricular dysfunction. Genetic expression was compared in EAT across all pre-HF and normal phenotypes, revealing small genetic changes in the form of 18 differentially expressed genes in ACC/AHA Stage A vs. Stage B. Conclusions The roles of subcutaneous and epicardial fat are clearly different. We highlight the gene expression difference in search of potential modifiers of HF progress. The true implications of our findings should be corroborated in other studies since HF ACC/AHA stage B patients are common and carry a considerable risk for progression to symptomatic HF.

Abstract The COVID-19 pandemic affected countries across the globe, demanding drastic public health policies to mitigate the spread of infection, which led to economic crises as a collateral damage. In this work, we investigate the impact of human mobility, described via international commercial flights, on COVID-19 infection dynamics on a global scale. We developed a graph neural network (GNN)-based framework called Dynamic Weighted GraphSAGE (DWSAGE), which operates over spatiotemporal graphs and is well-suited for dynamically changing flight information updated daily. This architecture is designed to be structurally sensitive, capable of learning the relationships between edge features and node features. To gain insights into the influence of air traffic on infection spread, we conducted local sensitivity analysis on our model through perturbation experiments. Our analyses identified Western Europe, the Middle East, and North America as leading regions in fueling the pandemic due to the high volume of air traffic originating or transiting through these areas. We used these observations to propose air traffic reduction strategies that can significantly impact controlling the pandemic with minimal disruption to human mobility. Our work provides a robust deep learning-based tool to study global pandemics and is of key relevance to policymakers for making informed decisions regarding air traffic restrictions during future outbreaks.

Abstract Aims The prevalence of iron deficiency (ID) in newly diagnosed heart failure (HF) and the progression of ID in patients after initiation of HF therapy are unknown. We aimed to describe the natural trajectory of ID in patients with new onset HF during the first year after HF diagnosis, assessing associations between ID, clinical factors, and quality of life (QoL). Methods and results A prospective cohort of patients with new onset HF in hospitals or outpatient clinics at five major hospitals in Stockholm, Sweden, during 2015–2018 were analysed with clinical assessment, electrocardiogram, blood samples including iron levels, Minnesota living with heart failure questionnaire (MLHFQ), and echocardiogram at baseline and after 12 months. Of 547 patients with new‐onset HF, 482 (88%) had complete iron data at baseline. Median age was 70 years (interquartile range 61–77) and 311 (65%) were men; 55% of patients had ejection fraction (EF) ≤ 40%, 19% had EF 41–49%, and 26% had HF with preserved EF (HFpEF) [Correction added on 26 June 2024, after first online publication: The ‘Mean age was 70 years’ has been corrected to ‘Median age was 70 years’ in this version.]. At baseline, 163 patients (34%) had ID defined as ferritin

Abstract Background Previous research has suggested that alternative (respiratory) care providers (ACP) may provide affordable, accessible care for sleep-disordered breathing (SDB) that decreases wait-times and improves clinical outcomes. The objective of this study was to compare ACP-led and sleep physician-led care for SDB on patient reported outcome and experiences, with a focus on general and health-related quality of life, sleepiness, and patient satisfaction. Methods We conducted a secondary analysis of a randomized trial in which participants with severe SDB were assigned to either ACP-led or physician-led management. We created longitudinal linear mixed models to assess the impacts of treatment arm and timepoint on total and domain-level scores of multiple patient-reported outcome measures and patient-reported experience measures. Results Patients in both treatment arms (ACP-led n = 81; sleep-physician = 75) reported improved outcomes on the Sleep Apnea Quality of Life Index, Health Utilities Index, and Epworth Sleepiness Scale. Patients in each group had similar and clinically meaningful improvements on domains assessing cognition, emotion, and social functioning. The linear mixed models suggested no significant difference between treatment arms on the patient-reported outcomes. However, scores significantly improved over time. Conclusions Management of SDB using ACPs was comparable to physician-led care, as measured bypatient-reported outcome and experience measures. While loss to follow-up limits our findings, these results provide some support for the use of this novel health service delivery model to improve access to high quality SDB care. Clinical trial registration This is analysis of data from the study registered Clinicaltrials.gov (NCT02191085).

Abstract Background Lynch syndrome represents the most common hereditary cause of both colorectal and endometrial cancer. It is caused by defects in mismatch repair genes, as well as EPCAM. Universal screening of colon tumors for Lynch syndrome via microsatellite instability (MSI) and/or immunohistochemistry (IHC) can identify patients and families at risk to develop further cancers and potentially impact surveillance and treatment options. The approach to implementation of universal screening, taking ethical considerations into account, is critical to its effectiveness, with patient perspectives providing valuable insight. Methods Patients whose colon tumors underwent universal screening at Penn State Hershey Medical Center over a period of 2.5 years were mailed a survey on universal screening in 2017. Along with the survey, they received a recruitment letter and a summary explanation of research. The survey included both multiple choice and free-response questions that covered topics including respondent knowledge of Lynch syndrome, attitudes toward universal screening and experiences with the screening protocol as implemented. Results Sixty-six of 297 possible patients (22.2%) responded to the survey, including 13 whose screening results raised concern for Lynch syndrome. 75.8% of respondents supported universal tumor screening without informed consent. 92.4% preferred receiving screening results regardless of outcome. Respondents described benefits to screening for themselves and their families. Conclusions While broadly supporting universal tumor screening without informed consent, respondents also wanted more information shared about the screening policy, as well as their results. These patient preferences should be one of many factors considered when implementing universal screening and can also inform practices regarding both tumor profiling and universal genetic testing, which is becoming more prevalent.

Background and objective: The depth of the prostate-specific antigen (PSA) decline after androgen receptor pathway inhibitor (ARPI) treatment combined with androgen deprivation therapy for patients with metastatic hormone-sensitive prostate cancer (mHSPC) may affect prognosis. The primary objective in our study was the correlation between the PSA response at 3 mo and radiologic progression-free survival (rPFS) at 24 mo. Three groups were defined according to the PSA decline: complete response (PSA ≤0.02 ng/ml), partial response (PSA >0.02 and ≤0.2 ng/ml), and incomplete response (PSA >0.2 ng/ml). Secondary objectives were correlation between the PSA response at 3 mo and overall survival, and the development of a model predicting complete PSA response. Methods: We conducted a retrospective multicenter study of patients with mHSPC treated with apalutamide from May 2018 to September 2023 registered in the Real-World Evidence APA registry across 20 centers. Key findings and limitations: We included 633 patients with mHSPC. The median age at diagnosis was 68 yr (interquartile range [IQR] 63–75) and median PSA was 16 ng/ml (IQR 7.5–64). Some 63% of the short had low-volume disease, 51% had de novo disease, 48% had recurrent disease. At 3 mo, 27% had a complete response, 42% a partial response, and 31% an incomplete response, with corresponding rRFS rates at 24 mo of 92%, 86%, and 63%. According to the predictive model, a complete PSA response at 3 mo was associated with the use of next-generation imaging and PSA

Abstract Transforming Growth Factor Beta1 (TGF-β1) signaling is upregulated in Chronic Obstructive Pulmonary disease (COPD), smokers, and people living with HIV. Cigarette smoking and HIV are also independent risk factors for COPD. Chronic inflammation is a hallmark of COPD. However, the underlying mechanisms remain unknown. Previous research has suggested that TGF-β1 alters the airway epithelial microRNAome and transcriptome, potentially contributing to lung inflammation. The Lactoperoxidase (LPO) system is an integral component of innate immunity within the airway. LPO plays a crucial role in host defense by catalyzing the oxidation of thiocyanate to hypothiocyanite in the presence of hydrogen peroxide (H2O2), generating a potent antibacterial and antiviral agent. Additionally, the LPO system potentially aids in maintaining cellular redox balance by reducing the levels of H2O2, thus mitigating oxidative stress within the airway epithelium. LPO dysfunction can impair immune responses and exacerbate inflammatory processes in respiratory diseases. In this study, primary bronchial epithelial cells and bronchial cell lines were treated with TGF-β1 and exposed to cigarette smoke to characterize the effect of these factors on LPO and their downstream effects. RT-qPCR and Western Blot were applied to quantify mRNA and proteins’ expression. The levels of H2O2 were detected using the Amplex Red Assay. Magnetofection and transfection were applied to probe the effect of miR-449b-5p. Staining procedures using the MitoTracker Green and C12FDG dyes were used to establish mitochondria mass and senescence. The levels of pro-inflammatory cytokines were measured via Luminex assays. We found that TGF-β1 and cigarette smoke suppressed airway LPO expression, increasing H2O2 levels. This increase in H2O2 had downstream effects on mitochondrial homeostasis, epithelial cellular senescence, and the pro-inflammatory cytokine response. We demonstrate for the first time that airway LPO is regulated by TGF-β1-induced miRNA-mediated post-transcriptional silencing through miR-449b-5p in the lungs. Further, we identify and validate miR-449-5p as the candidate miRNA upregulated by TGF-β1, which is involved in LPO suppression. This paper demonstrates a new mechanism by which TGF-β1 can lead to altered redox status in the airway.

Abstract Background Coronary artery disease (CAD) confers increased risks of premature mortality, non-fatal morbidity, and significant impairment in functional status and health-related quality of life. Routine administration of electronic patient-reported outcome measures (PROMs) and its real time delivery to care providers is known to have the potential to inform routine cardiac care and to improve quality of care and patient outcomes. This study describes a user-centered development and evaluation of the Alberta Provincial Project for Outcomes Assessment (APPROACH) electronic Patient Reported Outcomes Measurement (e-PROM) system. This e-PROM system is an electronic system for the administration of PROMs to patients with CAD and the delivery of the summarized information to their care providers to facilitate patient-physician communication and shared decision-making. This electronic platform was designed to be accessible via web-based and hand-held devices. Heuristic and user acceptance evaluation were conducted with patients and attending care providers. Results The APPROACH e-PROM system was co-developed with patients and care providers, research investigators, informaticians and information technology experts. Five PROMs were selected for inclusion in the online platform after consultations with patient partners, care providers, and PROMs experts: the Seattle Angina Questionnaire, Patient Health Questionnaire, EuroQOL, and Medical Outcomes Study Social Support Survey, and Self-Care of Coronary Heart Disease Inventory. The heuristic evaluation was completed by four design experts who examined the usability of the prototype interfaces. User acceptance testing was completed with 13 patients and 10 cardiologists who evaluated prototype user interfaces of the e-PROM system. Conclusion Both patients and physicians found the APPROACH e-PROM system to be easy to use, understandable, and acceptable. The APPROACH e-PROM system provides a user-informed electronic platform designed to incorporate PROMs into the delivery of individualized cardiac care for persons with CAD.

This review illuminates established knowledge of root–arbuscular mycorrhizal fungi (AMF)–plant mutualism to study the uptake of phosphorus (P) as a critical element for plant nutrition. We focus on P cycling, underscoring the role of AMF in enhancing P acquisition and plant resilience in the rhizosphere. The role(s) of plant roots, root exudates, and biomolecules in relevant soil processes is emphasized in this manuscript. Enhancing P uptake efficiency through AMF interaction presents a promising avenue for sustainable agriculture, with future research opportunities focusing on understanding underlying mechanisms and developing innovative technologies as a need to transition from the use of AMF as a biofertilizer or as an inoculation alternative for seeds to being an inspiration for the development of technology adapted to different crops. This is important to promote responsible agricultural practices and improve crop yields. We provide definitions of key terms and concepts for one of the best-known natural sustainable phosphorus systems. This manuscript illuminates and aims to inspire technology development to overcome the challenge of plant nutrition under P scarcity conditions.

Janus-type nanoparticles are important because of their ability to combine distinct properties and functionalities in a single particle, making them extremely versatile and valuable in various scientific, technological, and industrial applications. In this work, bimetallic silver–palladium Janus nanoparticles were obtained for the first time using the inert gas condensation technique. In order to achieve this, an original synthesis equipment built by Mantis Ltd. was modified by the inclusion of an additional magnetron in a second chamber, which allowed us to use two monometallic targets to sputter the two metals independently. With this arrangement, we could find appropriate settings at room temperature to promote the synthesis of bimetallic Janus nanoparticles. The structural properties of the resulting nanoparticles were investigated by transmission electron microscopy (TEM), and the chemical composition was analyzed by TEM energy dispersive spectroscopy (TEM-EDS), which, together with structural analysis, confirmed the presence of Janus-type nanostructures. Results of molecular dynamics and TEM simulations show that the differences between the crystalline structures of the Pd and Ag regions observed in the TEM micrographs can be explained by small mismatches in the orientations of the two regions of the particle. A density functional theory structural aims to understand the atomic arrangement at the interface of the Janus particle.

Abstract Protein design and engineering are evolving at an unprecedented pace leveraging the advances in deep learning. Current models nonetheless cannot natively consider non-protein entities within the design process. Here, we introduce a deep learning approach based solely on a geometric transformer of atomic coordinates and element names that predicts protein sequences from backbone scaffolds aware of the restraints imposed by diverse molecular environments. To validate the method, we show that it can produce highly thermostable, catalytically active enzymes with high success rates. This concept is anticipated to improve the versatility of protein design pipelines for crafting desired functions.

Abstract Background Mental health conditions affect one in seven young people and research suggests that current mental health services are not meeting the needs of most children and youth. Learning health systems are an approach to enhancing services through rapid, routinized cycles of continuous learning and improvement. Patient-reported outcome measures provide a key data source for learning health systems. They have also been shown to improve outcomes for patients when integrated into routine clinical care. However, implementing these measures into health systems is a challenging process. This paper describes a protocol for a formative evaluation of the implementation of patient-reported measures in a newly operational child and adolescent mental health centre in Calgary, Canada. The purpose is to optimize the collection and use of patient-reported outcome measures. Our specific objectives are to assess the implementation progress, identify barriers and facilitators to implementation, and explore patient, caregivers and clinician experiences of using these measures in routine clinical care. Methods This study is a mixed-methods, formative evaluation using the Consolidated Framework for Implementation Research. Participants include patients and caregivers who have used the centre’s services, as well as leadership, clinical and support staff at the centre. Focus groups and semi-structured interviews will be conducted to assess barriers and facilitators to the implementation and sustainability of the use of patient-reported outcome measures, as well as individuals’ experiences with using these measures within clinical care. The data generated by the patient-reported measures over the first five months of the centre’s operation will be analyzed to understand implementation progress, as well as validity of the chosen measures for the centres’ population. Discussion The findings of this evaluation will help to identify and address the factors that are affecting the successful implementation of patient-reported measures at the centre. They will inform the co-design of strategies to improve implementation with key stakeholders, which include patients, clinical staff, and leadership at the centre. To our knowledge, this is the first study of the implementation of patient-reported outcome measures in child and adolescent mental health services and our findings can be used to enhance future implementation efforts in similar settings.

Objetives. Bacterial resistance to antibiotics is a public health problem, however, few studies are performed in natural water ecosystems in middle-low-income countries. The objective of this study was to evaluate the presence and sensitivity to antimicrobials of Escherichia coli strains isolated from 24 irrigation water samples from the Rimac River in eastern Lima. Materials and methods. E.coli were identified by PCR. Antibiotic susceptibility was determined by disk diffusion method. The extended-spectrum beta-lactamase (ESBL), quinolones and virulence involved genes were determined by PCR. Results. All samples exceeded the permissible limits established in the Environmental Quality Standards for vegetable irrigation. Of the 94 strains, 72.3% showed resistance to at least one antibiotic, 24.5% were multidrug-resistant (MDR), and 2.1% were extremely drug resistant. The highest percentages of resistance were observed against nalidixic acid (50%), trimethoprim-sulfamethoxazole (35.5%) and ciprofloxacin (20.4%). Among the isolates, 3.2% presented ESBL phenotype related to blaCTX-M-15 gene. The transferable mechanisms of resistance to quinolones, qnrB were more frequent (20.4%), and 2.04% had the qnrS. It was determined that 5.3% were diarrheagenic E. coli and of these, 60% were enterotoxigenic E. coli, 20% were enteropathogenic E. coli and 20% were enteroaggregative E. coli. Conclusions. Our results show the existence diarrheagenic pathotypes in water used to irrigate fresh produce and highlights the presence of ESBL-producers and MDR E. coli, demonstrating the role that irrigation water plays in disseminating resistance genes in Peru.

Abstract The association of postpartum cardiac reverse remodeling (RR) with urinary proteome, particularly in pregnant women with cardiovascular (CV) risk factors who show long-term increased risk of cardiovascular disease and mortality is unknown. We aim to profile the urinary proteome in pregnant women with/without CV risk factors to identify proteins associated with postpartum RR. Our study included a prospective cohort of 32 healthy and 27 obese and/or hypertensive and/or diabetic pregnant women who underwent transthoracic echocardiography, pulse-wave-velocity, and urine collection at the 3rd trimester and 6 months postpartum. Shotgun HPLC–MS/MS profiled proteins. Generalized linear mixed-effects models were used to identify associations between urinary proteins and left ventricle mass (LVM), a surrogate of RR. An increase in arterial stiffness was documented from 3rd trimester to 6 months after delivery, being significantly elevated in women with CV risk factors. In addition, the presence of at least one CV risk factor was associated with worse LVM RR. We identified 6 and 11 proteins associated with high and low LVM regression, respectively. These proteins were functionally linked with insulin-like growth factor (IGF) transport and uptake regulation by IGF binding-proteins, platelet activation, signaling and aggregation and the immune system’s activity. The concentration of IGF-1 in urine samples was associated with low LVM regression after delivery. Urinary proteome showed a predicting potential for identifying pregnant women with incomplete postpartum RR.

Abstract Street food sector is an important component of the food distribution system in many cities. However, foods exposed for sale on the roadside are generally associated with conditions that favors its potential microbiological contamination. In this study, the microbiological quality of 118 ready-to-eat street foods sold in the metropolitan area of Lisbon, Portugal was evaluated. Mesophilic aerobic bacteria, yeasts, moulds, Enterobacteriaceae and Escherichia coli were used as spoilage/hygiene indicators. Listeria monocytogenes, Salmonella spp., coagulase-positive staphylococci (CPS), Clostridium perfringens, Bacillus cereus and E. coli pathotypes implicated in gastrointestinal disease were used as food safety/hygiene indicators. Thirty-five (29.7%) of the samples were classified as satisfactory, 29 (24.6%) as questionable and 51 (43.2%) as unsatisfactory. Three samples (2.6%) were unsatisfactory/ potentially dangerous, due to the presence of the L. monocytogenes > 102 cfu/g and/or B. cereus > 105 and/or CPS > 104. B. cereus genes encoding causative toxins were detected in the strains isolated from two samples containing > 105 cfu/g. Salmonella spp., Clostridium perfringens and pathogenic E. coli were not detected in any of the examined samples. CPS was detected in 26.3% of the samples. A significant relationship between microbiological quality and food groups, with the increase of questionable and unsatisfactory classifications for those samples including raw components, like fruits and vegetables, was observed (Fisher-Freeman-Halton = 29.01, p

Abstract Fair allocation of funding in multi-centre clinical studies is challenging. Models commonly used in Germany - the case fees (“fixed-rate model”, FRM) and up-front staffing and consumables (“up-front allocation model”, UFAM) lack transparency and fail to suitably accommodate variations in centre performance. We developed a performance-based reimbursement model (PBRM) with automated calculation of conducted activities and applied it to the cohorts of the National Pandemic Cohort Network (NAPKON) within the Network of University Medicine (NUM). The study protocol activities, which were derived from data management systems, underwent validation through standardized quality checks by multiple stakeholders. The PBRM output (first funding period) was compared among centres and cohorts, and the cost-efficiency of the models was evaluated. Cases per centre varied from one to 164. The mean case reimbursement differed among the cohorts (1173.21€ [95% CI 645.68–1700.73] to 3863.43€ [95% CI 1468.89–6257.96]) and centres and mostly fell short of the expected amount. Model comparisons revealed higher cost-efficiency of the PBRM compared to FRM and UFAM, especially for low recruitment outliers. In conclusion, we have developed a reimbursement model that is transparent, accurate, and flexible. In multi-centre collaborations where heterogeneity between centres is expected, a PBRM could be used as a model to address performance discrepancies. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04768998 ; https://clinicaltrials.gov/ct2/show/NCT04747366 ; https://clinicaltrials.gov/ct2/show/NCT04679584 .

Abstract Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is considered a growing health concern. The majority of NTM-PD cases in Europe are caused by slow-growing mycobacteria (SGM). However, distinct radiological features of different SGM remain largely uninvestigated. We applied a previously described radiological score to a patient cohort consisting of individuals with isolation of different SGM. Correlations between clinical data, species and computed tomography (CT) features were examined by logistic and linear regression analyses, as well as over the course of time. Overall, 135 pulmonary CT scans from 84 patients were included. The isolated NTM-species were mainly Mycobacterium avium complex (MAC, n = 49), as well as 35 patients with non-MAC-species. Patients with isolation of M. intracellulare had more extensive CT findings compared to all other SGM species (coefficient 3.53, 95% Cl − 0.37 to 7.52, p = 0.075) while patients meeting the ATS criteria and not undergoing therapy exhibited an increase in CT scores over time. This study provides insights into differential radiological features of slow-growing NTM. While M. intracellulare exhibited a tendency towards higher overall CT scores, the radiological features were similar across different SGM. The applied CT score might be a useful instrument for monitoring patients and could help to guide antimycobacterial therapy.

Abstract Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, filtering water, controlling primary producers, and providing food for predators. Their differences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, efforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specific taxa to assessing the success of legislative and management restoration efforts.

Abstract Background The treatment of erythrodermic psoriasis (EP) is challenging. Biological therapies have shown promising results in the long‐term management of this clinical variant, but most of the current available evidence is based on single case reports and short case series. Objectives To determine the effectiveness and safety of ustekinumab (UST) in the treatment of EP under daily practice conditions. Methods We conducted a retrospective, observational, nationwide, multicenter cohort study of patients diagnosed with EP treated with UST under daily practice conditions with up to 3 years of follow‐up. Outcomes, such as the psoriasis area and severity index (PASI) and safety, were assessed at months 1, 4, 7, 13, 19, 25, 31 and 37 during treatment. “As observed” and “intention‐to‐treat last observation carried forward (ITT‐LOCF)” analyses were performed. Results Twenty‐eight patients were enroled in the study. Baseline mean PASI was 43.1. A sharp decrease in mean PASI was observed during the first 7 months, reaching a plateau that was maintained until the end of the 37‐month follow‐up. At 7 months, 61% and 43% of the patients achieved PASI ≤ 2 and PASI 0, respectively. At 25 months, 48 (39%) (“as observed”/ITT‐LOCF) of the patients achieved complete clearance. At 31 months, PASI 75, PASI 90 and PASI 100 were achieved in 95, 80 and 45 (79%, 64% and 39%) (“as observed”/ITT‐LOCF) of the patients, respectively. Eleven patients required treatment intensification by reducing the interval between doses. Treatment minimisation was performed in four patients. During the follow‐up, nine patients (32%) received systemic combination therapy at some point. Eight patients discontinued treatment mainly due to lack of effectiveness. UST presented a good safety profile. With a follow‐up of 69.25 patient/years, only three patients exhibited serious nondrug‐related adverse events. Conclusions Ustekinumab can be a fast, effective and safe alternative for the long‐term treatment of erythrodermic psoriasis.

Abstract The ocean response to Antarctic Ice Sheet (AIS) mass loss has been extensively studied using numerical models, but less attention has been given to the atmosphere. We examine the global atmospheric response to AIS meltwater in an ensemble of experiments performed using two fully coupled climate models under a pre‐industrial climate. In response to AIS meltwater, the experiments yield cooling from the surface to the tropopause over the subpolar Southern Ocean, warming in the Southern Hemisphere polar stratosphere, and cooling in the upper tropical troposphere. Positive feedbacks, initiated by disrupted ocean‐atmosphere heat exchange, result in a change in the top‐of‐atmosphere radiative balance caused primarily through surface and near‐surface albedo changes. Changes in the atmospheric thermal structure alter the jet streams aloft. The results highlight the global influence of AIS melting on the climate system and the potential for impacts on mid‐latitude climate patterns and delayed regional warming signals.

Gaucher disease (GD) is a lysosomal storage disorder (LSD) resulting from inherited glucocerebrosidase (GBA1) deficiency. GD diagnosis relies on GBA1 activity assays, typically employing 4-methylumbelliferyl-β-D-glucopyranoside (4MU-β-Glc) as fluorogenic substrate. However, these assays suffer from background 4MU release by the non-lysosomal GBA2 and cytosolic GBA3 enzymes. Here we developed GBA1-selective fluorogenic substrates by synthesizing a series of 6-O-acyl-4MU-β-Glc substrates with diverse fatty acid tails. Because of the chemical and enzymatic instability of the ester bonds, analogs of 6-O-palmitoyl-4MU-β-Glc (3) with different chemical linkages were synthesized. 6-O-alkyl-4MU-β-Glc 9, featuring an ether linkage, emerged as the most optimal GBA1 substrate, exhibiting both a low Km and compared to substrate 3 a high Vmax. Importantly, substrate 9 is not hydrolyzed by GBA2 and GBA3 and therefore acts as a superior substrate for GD diagnosis. Plants contain glycosyl phytosterols (campesterol, β-sitosterol, and sigmasterol) that may also be acylated at C-6. LC-MS/MS analysis revealed that 6-O-acylated and regular glycosylcholesterol (HexChol) tend to be increased in spleens of patients with GD. Moreover, significant increases in 6-O-acyl-glycosyl-phytosterols were detected in GD spleens. Our findings suggest uptake of (6-O-acyl)-glycosyl-phytosterols from plant food and subsequent lysosomal processing by GBA1, and comprise the first example of accumulation of an exogenous class of glycolipids in GD. Excessive exposure of rodents to glycosylated phytosterols has been reported to induce manifestations of Parkinson’s disease (PD). Further investigation is warranted to determine whether (6-O-acyl)-glycosyl-phytosterols could contribute to the enigmatic link between inherited defects in GBA1 and the risk for PD.

Introduction There are no established methods to identify children with atypical diabetes for further study. We aimed to develop strategies to systematically ascertain cases of atypical pediatric diabetes using electronic medical records (EMR).Research design and methods We tested two strategies in a large pediatric hospital in the USA. Strategy 1: we designed a questionnaire to rule out typical diabetes and applied it to the EMR of 100 youth with diabetes. Strategy 2: we built three electronic queries to generate reports of three atypical pediatric diabetes phenotypes: unknown type, type 2 diabetes (T2D) diagnosed

IntroductionThe importance of nurturing care for child development is well-established, and parents play a central role in providing this care. However, cultural values and traditions can influence child-rearing practices, and there are gaps in child welfare in Ecuador. Two research questions delve into caregivers’ definitions of nurturing care for children aged 0–5 and its alignment with World Health Organization’s concept.MethodsA qualitative methodology was applied to comprehensively explore caregivers’ perspectives and application of nurturing care across diverse cultural contexts in rural areas of Cotopaxi and Loja in Ecuador. Using snowball sampling primary caregivers, healthcare professionals, childcare workers, and community leaders were interviewed and participated in focus groups, examining its congruence with WHO’s Nurturing Care Framework for Early Childhood Development.ResultsWhile there is alignment with the WHO framework, the study reveals challenges such as a lack of awareness of the term “nurturing care” among participants. Findings also indicate issues in health communication, reliance on traditional medicine, and myths around nutritional practices. The role of technology in early learning is explored, noting both its advantages and disadvantages. Notably, preventive health activities were not mentioned, emphasizing a universal need for knowledge.ConclusionThis study urges tailored interventions for nurturing care, emphasizing success tied to robust healthcare and child protection. Urgency lies in cultural sensitivity, local adaptation, and targeted training for implementation. These insights contribute significantly to the global discourse, stressing the importance of context-specific approaches. Implications are crucial for policymakers, practitioners, and researchers dedicated to elevating care quality for vulnerable populations worldwide.

Background: Strengths-based and culturally sensitive approaches to Indigenous healthcare are much needed within the Canadian healthcare system. This is where allyship comes in. Allyship is loosely defined as the actions of an individual who strives to advance the interests of marginalized groups in which they are not a member. This study investigated the concept of allyship with healthcare providers who were community-identified allies providing care for Indigenous patients. Methods: Qualitative description methodology was utilized, and data was generated through semi-structured interviews with allies in and around the Edmonton area, in Canada. The interviews were conducted online, transcribed verbatim and then coded using thematic analysis. Results: Interviews were conducted with 13 allies (eight physicians, four allied health professionals and one nurse). The results were captured into three main themes. The meaning of allyship demonstrated how allyship must be determined by the community, and encapsulates authentic action and advocacy, as well as working to create positive healthcare experiences. The experience of being an ally included commitment to the allyship journey, embracing emotions, and facing and disrupting systemic barriers. Finally, cultivating allyship in healthcare necessitated building and maintaining meaningful relationships with Indigenous people, and ongoing training and education. Conclusion: The study results enabled a better understanding of how allies interact with their Indigenous patients within the confines of the healthcare system and could inform learning opportunities for those who seek to practice in a culturally humble way. In particular, transcending passive education and training modalities to include opportunities for real life interactions and the development of reciprocal relationships with Indigenous patients.

Abstract Navigating social‐ecological systems toward sustainable trajectories is an important challenge of the Anthropocene. Models of social‐ecological systems can increase our understanding of how social and ecological subsystems interact, their response to environmental changes, and how their dynamics may be altered by management interventions. However, the level of representational detail required for models to describe a particular social‐ecological system with high fidelity (i.e., accurately quantifying system dynamics) may hamper both the interpretability of model results and our ability to identify key processes and feedbacks within the system. In contrast, stylized models describe simplified interactions between a small subset of social‐ecological system elements. Stylized models are a useful tool to identify potential consequences of specific key processes and feedbacks on system functioning. However, the relatively low level of representational detail in these models limits their ability to deliver concrete management options for a particular social‐ecological system. Here, we describe how an exploratory modeling approach can utilize the strengths of stylized models before the construction of social‐ecological system models with high fidelity and representational detail. This exploratory modeling approach is an iterative strategy, with the initial steps comprising the development of stylized models informed by empirical observations. We illustrate this with two examples of stylized modeling of isolated and connected social‐ecological systems. Through repeated confrontation of alternative models with empirical data, exploratory modeling provides useful stepping stones toward the development of models that describe social‐ecological systems in increasingly specific settings with increasing levels of representational detail. When these latter types of models reach a high level of fidelity, they could be used for scenario‐based analyses and participatory decision‐making processes. At this stage, the conceptual insights previously obtained during the exploratory modeling phase may aid in the interpretation and communication of the outcomes of scenario‐based analyses. Hence, exploratory modeling aims to create a synergy between the insights obtained from stylized models and system‐specific, high‐fidelity models in order to generate a deep understanding of the drivers of social‐ecological system dynamics, and how to leverage these drivers to initiate desired changes.

Induced resistance (IR), which enables plants to increase their resilience against insect pests and microbial pathogens by promoting their own immunity, has been recognized for its value in crop protection schemes. Despite promising applications, the use of IR in crop protection has remained marginal compared with pesticides and single resistance genes. This review aims to shed light on this disparity by examining the scientific milestones achieved over the past decades for both internal (immunological) and external (ecological) IR strategies. The multifaceted advantages of IR, particularly its ability to provide broad-spectrum protection and enhance the nutritional and nutraceutical value of certain crops, are also discussed. The various obstacles hindering the widespread adoption of IR strategies are then revealed. After considering recent scientific discoveries and insights, potential solutions are proposed, including leveraging epigenetic approaches to understand the mechanisms involved in IR. By acknowledging that the future sustainability of crop protection is irreconcilable with single-use technologies, this review proposes taking advantage of the latest insights regarding the adaptive nature of the plant immune system and its ecological interactions to safely integrate IR into existing crop protection schemes. By emphasizing the need for comprehensive and holistic approaches to basic and translational research, this review sets the stage for leveraging IR alongside other strategies to foster a resilient, environmentally friendly, and economically viable future, thereby ensuring the health of crops.

ObjectiveThe quality of the relationship between persons with dementia and family carers influences health and quality-of-life outcomes. Little is known regarding those at higher risk of experiencing a decline in relationship quality, who could potentially benefit the most from interventions. We aimed to identify these risk profiles and explore the underlying factors.MethodsWe applied a latent profile analysis to relationship quality data from a 1-year follow-up of 350 dyads of persons with dementia and their informal carers from the Actifcare cohort in eight European countries. Assessments included sociodemographic, clinical, functional, psychosocial and quality-of-life measures. Relationship quality was assessed with the Positive Affect Index. A discriminant analysis explored factors influencing the risk profiles.ResultsThere were two relationship quality profiles among persons with dementia (gradually decreasing, 74.0%; low but improving, 26%) and two among carers (steadily poor, 57.7%; consistently positive, 42.3%). The ‘gradually decreasing’ profile (persons with dementia) was related to their levels of dependence and unmet needs, along with carers’ social distress and negative feelings, lower baseline RQ and sense of coherence. The ‘steadily poor’ profile (carers) was influenced by their social distress and negative feelings, lower sense of coherence and perceived social support. These two predominant profiles showed significant decreases in quality-of-life over one year.ConclusionsSpecific profiles of persons with dementia and their carers are at risk of worse relationship quality trajectories. By considering modifiable related factors (e.g., carers’ stress), our findings can help develop tailored, effective interventions.

Abstract Winter diapause consists of cessation of development that allows individuals to survive unfavourable conditions. Winter diapause may bear various costs and questions have been raised about the evolutionary mechanisms maintaining facultative diapause. Here, we explored to what extent a facultative winter diapause affects life-history traits and the transcriptome in the damselfly Ischnura elegans, and whether these effects were latitude-specific. We collected adult females at central and high latitudes and raised their larvae in growth chambers. Larvae were split into a non-diapausing and post-winter (diapausing) cohort, were phenotyped and collected for a gene expression analysis. At the phenotypic level, we found no difference in survival between the two cohorts, and the post-winter cohort was larger and heavier than the non-winter cohort. These effects were mostly independent of the latitude of origin. At the transcriptomic level, wintering affected gene expression with a small fraction of genes significantly overlapping across latitudes, especially those related to morphogenesis. In conclusion, we found clear effects of diapause on the phenotype but little evidence for latitudinal-specific effects of diapause. Our results showed a shared transcriptomic basis underpinning diapause demonstrated, here, at the intraspecific level and supported the idea of evolutionary convergence of the response to diapause across organisms.

Abstract SARS-CoV-2 is the causative agent of COVID-19. Timely and accurate diagnostic testing is vital to contain the spread of infection, reduce delays in treatment and care, and inform patient management. Optimal specimen type (e.g. nasal swabs or saliva), timing of sampling, viral marker assayed (RNA or antigen), and correlation with viral infectivity and COVID-19 symptoms severity remain incompletely defined. We conducted a field study to evaluate SARS-CoV-2 viral marker kinetics starting from very early times after infection. We measured RNA and antigen levels in nasal swabs and saliva, virus outgrowth in cell culture from nasal swabs, and antibody levels in blood in a cohort of 30 households. Nine household contacts (HHC) became infected with SARS-CoV-2 during the study. Viral RNA was detected in saliva specimens approximately 1–2 days before nasal swabs in six HHC. Detection of RNA was more sensitive than of antigen, but antigen detection was better correlated with culture positivity, a proxy for contagiousness. Anti-nucleocapsid antibodies peaked one to three weeks post-infection. Viral RNA and antigen levels were higher in specimens yielding replication competent virus in cell culture. This study provides important data that can inform how to optimally interpret SARS-CoV-2 diagnostic test results.

Abstract Despite abundant evidence demonstrating that platelets foster metastasis, anti-platelet agents have low therapeutic potential due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subject syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases via immune suppression. Genetic depletion and pharmacological targeting of the glycoprotein VI (GPVI) platelet-specific receptor in humanized mouse models efficiently reduce the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study demonstrates therapeutic efficacy when targeting animals bearing growing metastases. It further identifies GPVI as a molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.

Abstract Background The COVID-19 pandemic had and still have a major impact on adolescent mental health and consequently on suicidal behavior. However, few studies have investigated whether the pandemic has changed the patterns and the triggers of suicidality peaks in adolescents, e.g., seasonal patterns or family conflicts. We hypothesized that the pandemic modified suicidality rates: an increment of suicide attempts would be observed in the first semester of the academic year during COVID-19 pandemic compared to the same period of previous academic year; and the precipitating factors would be more related to social stressors during the pandemic school year. Methods A retrospective cross-sectional study was conducted to assess the precipitating factors, also including school-related factors and cognitive skills, of adolescent suicide attempters occurred in the first and second semesters of the year before the pandemic lockdown (study periods 1 and 2) and the year after (study periods 3 and 4). Results The sample consisted of 85 adolescents aged between 12 and 17 recruited consecutively from March 2019 to March 2021 at emergency ward because of suicide attempt. Forty-eight adolescents (55.3% of the sample) were attended before the lockdown (pre-pandemic group) and 38 (44.7%) the year after. The results showed a higher proportion of female suicide attempters in period 4 (Sept 2020-Feb 2021) respect to period 3 (Mar 2020-Aug 2020), i.e., pandemic semesters compared with the increment observed between period 2 and 1 (prepandemic semesters; Fisher’s exact test = 4.73; p = 0.026). The multinomial regression models showed a significant effect in the frequency of adolescents who attempted suicide (ratio χ2 = 15.19, p = 0.019), accounted by the differences between period 4 (Sept 2020-Feb 2021) and period 1 (Mar 2019-Aug 2019), with depressive symptoms being a significant contributing factor (Exp(b) = 0.93; p = 0.04). Additionally, social triggers and age were found to be significant risk factors for suicide attempts in the first semester of the pandemic academic year (period 4) compared to the same semester of the pre-pandemic year (period 2; Exp(b) = 0.16, p = 0.01, and Exp(b) = 1.88, p = 0.006, respectively). Conclusions During the pandemic, the decrement between first and second semester of the number of females attempting suicide was more pronounced than in the prepandemic school year -though this findings lacked statistical power due to very limited sample size-. Change in the frequency of adolescent attempting suicide in the different school periods was associated with greater severity of depressive symptoms. Social relations in back-to-school after the lockdown were also associated with the number of adolescents attempting suicide.

Background and objective: The treatment landscape of metastatic prostate cancer (mPCa) has evolved significantly over the past two decades. Despite this, the optimal therapy for patients with mPCa has not been determined. This systematic review identifies available predictive models that assess mPCa patients’ response to treatment. Methods: We critically reviewed MEDLINE and CENTRAL in December 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Only quantitative studies in English were included with no time restrictions. The quality of the included studies was assessed using the PROBAST tool. Data were extracted following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews criteria. Key findings and limitations: The search identified 616 citations, of which 15 studies were included in our review. Nine of the included studies were validated internally or externally. Only one study had a low risk of bias and a low risk concerning applicability. Many studies failed to detail model performance adequately, resulting in a high risk of bias. Where reported, the models indicated good or excellent performance. Conclusions and clinical implications: Most of the identified predictive models require additional evaluation and validation in properly designed studies before these can be implemented in clinical practice to assist with treatment decision-making for men with mPCa. Patient summary: In this review, we evaluate studies that predict which treatments will work best for which metastatic prostate cancer patients. We found that existing studies need further improvement before these can be used by health care professionals.

Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in “real-life” patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

Abstract Quantitative phase imaging (QPI) has become a vital tool in bioimaging, offering precise measurements of wavefront distortion and, thus, of key cellular metabolism metrics, such as dry mass and density. However, only a few QPI applications have been demonstrated in optically thick specimens, where scattering increases background and reduces contrast. Building upon the concept of structured illumination interferometry, we introduce Gradient Retardance Optical Microscopy (GROM) for QPI of both thin and thick samples. GROM transforms any standard Differential Interference Contrast (DIC) microscope into a QPI platform by incorporating a liquid crystal retarder into the illumination path, enabling independent phase-shifting of the DIC microscope's sheared beams. GROM greatly simplifies related configurations, reduces costs, and eradicates energy losses in parallel imaging modalities, such as fluorescence. We successfully tested GROM on a diverse range of specimens, from microbes and red blood cells to optically thick (~ 300 μm) plant roots without fixation or clearing.

Abstract Background In order to ensure adequate radiation protection of critical groups such as staff, caregivers and the general public coming into proximity of nuclear medicine (NM) patients, it is necessary to consider the impact of the radiation emitted by the patients during their stay at the hospital or after leaving the hospital. Current risk assessments are based on ambient dose rate measurements in a single position at a specified distance from the patient and carried out at several time points after administration of the radiopharmaceutical to estimate the whole-body retention. The limitations of such an approach are addressed in this study by developing and validating a more advanced computational dosimetry approach using Monte Carlo (MC) simulations in combination with flexible and realistic computational phantoms and time activity distribution curves from reference biokinetic models. Results Measurements of the ambient dose rate equivalent Ḣ * (10) at 1 m from the NM patient have been successfully compared against MC simulations with 5 different codes using the ICRP adult reference computational voxel phantoms, for typical clinical procedures with 99mTc-HDP/MDP, 18FDG and Na131I. All measurement data fall in the 95% confidence intervals, determined for the average simulated results. Moreover, the different MC codes (MCNP-X, PHITS, GATE, GEANT4, TRIPOLI-4®) have been compared for a more realistic scenario where the effective dose rate Ė of an exposed individual was determined in positions facing and aside the patient model at 30 cm, 50 cm and 100 cm. The variation between codes was lower than 8% for all the radiopharmaceuticals at 1 m, and varied from 5 to 16% for the face-to face and side-by-side configuration at 30 cm and 50 cm. A sensitivity study on the influence of patient model morphology demonstrated that the relative standard deviation of Ḣ * (10) at 1 m for the range of included patient models remained under 16% for time points up to 120 min post administration. Conclusions The validated computational approach will be further used for the evaluation of effective dose rates per unit administered activity for a variety of close-contact configurations and a range of radiopharmaceuticals as part of risk assessment studies. Together with the choice of appropriate dose constraints this would facilitate the setting of release criteria and patient restrictions.

Abstract Classifying diabetes at diagnosis is crucial for disease management but increasingly difficult due to overlaps in characteristics between the commonly encountered diabetes types. We evaluated the prevalence and characteristics of youth with diabetes type that was unknown at diagnosis or was revised over time. We studied 2073 youth with new-onset diabetes (median age [IQR] = 11.4 [6.2] years; 50% male; 75% White, 21% Black, 4% other race; overall, 37% Hispanic) and compared youth with unknown versus known diabetes type, per pediatric endocrinologist diagnosis. In a longitudinal subcohort of patients with data for ≥ 3 years post-diabetes diagnosis (n = 1019), we compared youth with steady versus reclassified diabetes type. In the entire cohort, after adjustment for confounders, diabetes type was unknown in 62 youth (3%), associated with older age, negative IA–2 autoantibody, lower C-peptide, and no diabetic ketoacidosis (all, p < 0.05). In the longitudinal subcohort, diabetes type was reclassified in 35 youth (3.4%); this was not statistically associated with any single characteristic. In sum, among racially/ethnically diverse youth with diabetes, 6.4% had inaccurate diabetes classification at diagnosis. Further research is warranted to improve accurate diagnosis of pediatric diabetes type.

Abstract Nowadays, social networks have taken on an irreplaceable role as sources of information. Millions of people use them daily to find out about the issues of the moment. This success has meant that the amount of content present in social networks is unmanageable and, in many cases, fake or non-credible. Therefore, a correct pre-processing of the data is necessary if we want to obtain knowledge and value from these data sets. In this paper, we propose a new data pre-processing technique based on Big Data that seeks to solve two of the key concepts of the Big Data paradigm, data validity and credibility of the data and volume. The system is a Spark-based filter that allows us to flexibly select credible users related to a given topic under analysis, reducing the volume of data and keeping only valid data for the problem under study. The proposed system uses the power of word embeddings in conjunction with other text mining and natural language processing techniques. The system has been validated using three real-world use cases.

Abstract The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood–brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.