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Although research on the home literacy environment and its impact on early literacy has long focused on mothers, the past decade has seen a shift in scholarly attention to the role of fathers. Building on this shift, we examined whether the nature of parent-child interactions during shared storybook reading varies with parent gender, child gender and the interaction between the two, and we analysed whether possible differences in the nature of mother- and father-child interactions are related to story comprehension. We made video observations of mothers and fathers within 36 relatively highly educated families reading a storybook with their kindergartener (age 4 - 5) and registered the use of cognitively challenging (i.e. decontextualized) talk during these activities. After each shared reading session, we additionally administered a test assessing children's understanding of the story being read. Two-way mixed ANOVA's revealed no effects of parent gender or child gender on either the use of cognitively challenging talk or children's story comprehension, nor did we find interaction effects of parent and child gender. The extent of cognitively challenging talk was significantly correlated to children's comprehension scores for fathers, but not for mothers. This correlation seems to have masked another association, however: when correlations were computed separately for girls and boys, we found that the proportion of cognitively challenging utterances of both parents was correlated to comprehension scores for boys, but not for girls. The absence of parent gender effects provides further insights into the way mothers and fathers shape interactions during shared reading, but also stresses the need for studies with larger, more diverse samples. The observation that more frequent use of cognitively challenging talk was paralleled by better story comprehension for boys invites further research on the specific effects of shared reading for boys.

Climate change is a global existential threat with far-reaching implications for natural ecosystems, biodiversity, and human societies. Adapting to and mitigating climate change require global cooperation and participation from all mindsets and belief systems, including the traditionally western weather, water, and climate enterprise (WWCE), faith-based understandings (FBUs), and Indigenous Knowledges (IKs). Epistemological differences and language barriers between knowledges and the historical marginalization and exploitation of IKs by western ideologies and some FBUs make coproduction and relationship building challenging. Acknowledging their historical tensions and distinctions, there is meaningful overlap between the WWCE, FBUs, and IKs on environmental stewardship, justice, and mental health. This article highlights three themes at the intersection of FBUs, IKs, and environmentalism: 1) increasing faith- based and Indigenous community resilience to weather extremes; 2) developing kindergarten through grade 12 (K-12) and collegiate weather, water, and climate education that weaves FBUs and IKs; and 3) increasing communication flows between weather, water, and climate science, and faith-based and Indigenous communities. These initiatives aim to foster relationships and trust between the WWCE, faith-based, and Indigenous communities; transform the WWCE into a multiknowledge enterprise; and promote a climate-resilient society. The American Meteorological Society's Committee on Spirituality, Multifaith Outreach, and Science (COSMOS) plays a pivotal role in facilitating dialogue and collaboration on these themes while acknowledging distinctions and historical tensions between FBUs, IKs, and the WWCE. Collaborative efforts between the WWCE, faith- based, and Indigenous communities hold immense potential for addressing climate challenges, fostering resilience, and building a more inclusive and sustainable future grounded in mutual respect and understanding. SIGNIFICANCE STATEMENT: This article addresses how weaving faith-based understandings (FBUs) and Indigenous Knowledges (IKs) into the weather, water, and climate enterprise (WWCE) can effectively tackle climate change, extreme weather, and other environmental challenges. Emphasizing the need for a shift in mindset and community dialogue, the path to adaptation begins with raising awareness and fostering discussions that bridge science and societal values. This includes acknowledging the historical tensions that exist between FBUs, IKs, and western science and being honest about the challenges and distinctions that arise from these tensions. Through partnerships highlighted between the American Meteorological Society (AMS), Indigenous groups, and multifaith organizations, we see practical outcomes: enhanced weather preparedness, improved mental well-being, holistic environmental solutions, and informed policymaking. These collaborations are crucial for building a resilient and sustainable future by connecting community strengths through a multiknowledge scientific and cultural approach. KEYWORDS: Climate change; Adaptation; Communications/ decision making; Education; Indigenous knowledge; Resilience, 1. Introduction Our changing climate presents an urgent, global, and existential threat with profound implications for natural ecosystems, biodiversity, and human societies worldwide (IPCC 2022). The urgent need to confront [...]

ABSTRACT: Targeted reproductive management (TRM) aims to improve the fertility efficiency of the dairy herd by applying group-level management strategies based on expected reproductive performance. Key to the utility of TRM is the accuracy with which an animal's reproductive performance can be predicted. Automatic milking systems (AMS) allow for the collection of data relating to milk quantity, quality, and robot visit behavior throughout the transition period. In addition to this, auxiliary data sources, such as rumination and activity monitors, as well as historical cow-level data, are often readily available. The utility of this data for the prediction of fertility has not been previously explored. The first objective of this study was to assess the accuracy with which the likelihood of expression of estrus between 22 and 65 DIM and conception to first insemination between 22 and 80 DIM could be predicted using data collected by AMS from 1 to 21 DIM. Our second objective was to assess the change in model performance following the addition of 2 auxiliary data sources. Using data derived solely from the AMS (RBT dataset) a binary random forest classification model was constructed for both outcomes of interest. The performance of these models was compared with models constructed using AMS data in conjunction with 2 auxiliary sources (RBT+ dataset). Expression of estrus was classified with an area under the receiver operator curve (AUC-ROC) of 0.6 and 0.65, conception to first insemination with an AUC-ROC of 0.56 and 0.62 for the RBT and RBT+ datasets, respectively. No statistically significant improvement in classification accuracy was achieved by the addition of auxiliary data sources. This is the first study to report the utility of data collected by AMS for the prediction of reproductive performance. Though the performance described is comparable with previously reported models, their utility for the implementation of TRM is limited by poor classification accuracy within key subgroups. Of note within this study is the failure of the addition of auxiliary data sources to increase the accuracy of prediction over models built using AMS data alone. We discuss the advantages and limitations the integration of additional data sources imposes on model training and deployment and suggest alternative methods to improve performance while preserving model parsimony.

Processed fecal sludge generated from a sludge treatment plant rich of organic content, micronutrients, and several heavy metals that might potentially exist. Composting process recognized as a promising and cost-effective method to improve the sludge quality. The composting process was carried out in this study by using modified Compost Bag with processed sludge from fecal sludge treatment plant as the main material and organic waste and dry leaves as co-composting materials. The macro-micronutrients and heavy metal concentration of the produced compost were further analyzed. The potential application was also considered by indulging the risk assessment. The main and co-composting materials were investigated in three different ratios of processed fecal sludge (S), organic waste (OW), and dry leaves (DL) to get the optimum composition that meet the compost quality standard. Compost R2 with the ratio of 50S: 25OW: 25DL as an optimum composition which resulted good quality compost with the C/N ratio of 10.29, Total P2O5 about 2.45%, Total K2O of 0.38%, and the Cu removal up to 91.17%. The produced Compost R2 has met the compost quality standard with Hazard Quotient (HQ) for non-carcinogenic effects less than 1 revealed no potential for disease-causing effects thus safe to be used in daily life.

A Educação necessita abordar as atividades científicas e tecnológicas de modo a proporcionar aos estudantes meios de compreender e avaliar suas influências sobre diversos parâmetros que caracterizam a sociedade. Neste sentido, a educação sob a perspectiva Ciência,Tecnologia e Sociedade (CTS), pode promover a adoção de valores e atitudes que lhes permitam interpretar e se posicionar frente a essas atividades tendo em vista os efeitos da globalização, dos sistemas de produção e consumo e a necessidade de transformarmos a realidade social e ambiental, buscando uma melhor qualidade de vida e a sustentabilidade. Portanto, a investigação em tela tem objetivo de identificar a Representação Social (RS) de estudantes da educação básica sobre o ambiente marinho, utilizando as contribuições de Moscovici e a teoria do núcleo central proposta por Abric. Do ponto de vista metodológico, procurou-se identificar a RS de 299 estudantes que se encontram na faixa etária entre 11 e 16 anos, regularmente matriculados no 7ºano, 8ºano e 9ºano do ensino fundamental, de duas escolas brasileiras. Como instrumento de coleta de dados os estudantes tinham que responder à seguinte questão: Ao pensar nos mares e oceanos, quais são as seis primeiras palavras que vem à sua mente? A partir da análise dos dados percebeu-se que mesmo sendo o Brasil um país conhecido por ter uma extensa área litorânea, as respostas dos estudantes revelam a existência de um distanciamento considerável em relação a tal ambiente.

Background: Glycoprotein (GP)VI is a platelet-specific collagen receptor required for platelet activation during hemostasis. Platelet reactivity toward collagen is routinely assessed during diagnostic workup of platelet disorders. GPVI can be activated by inducing receptor clustering with suspensions of fibrillar collagen or synthetic cross-linked collagen-related peptide (CRP-XL). However, these suspensions are poorly standardized or difficult to produce. Nanobodies are small recombinant camelid-derived heavy-chain antibody variable regions. They are highly stable, specific, and ideal candidates for developing a stable GPVI agonist for diagnostic assays. Objectives: Develop a stable nanobody-based GPVI agonist. Methods: Nanobody D2 (NbD2) was produced as dimers and purified. Tetramers were generated via C-terminal fusion of dimers with click chemistry. Nanobody constructs were functionally characterized with light transmission aggregometry (LTA) in platelet-rich plasma and whole blood flow cytometry. Diagnostic performance was assessed in patients with inherited platelet function disorders with LTA and flow cytometry. Results: NbD2 was specific for human platelet GPVI. Dimers did not result in platelet activation in LTA or flow cytometry settings and fully inhibited CRP-XL-induced P-selectin expression and fibrinogen binding in whole blood and attenuated collagen-induced platelet aggregation in platelet-rich plasma. However, NbD2 tetramers caused full platelet aggregation, as well as P-selectin expression and fibrinogen binding. NbD2 tetramers were able to discriminate between inherited platelet function disorder patients and healthy controls based on fibrinogen binding, similar to CRP-XL. Conclusion: Nanobody tetramers to GPVI induce platelet activation and can be used to assess the GPVI pathway in diagnostic assays.

Background: Eradicating inhibitors to restore the effectiveness of Factor VIII (FVIII) is a desirable treatment goal for People with Severe Hemophilia A (PwSHA) and inhibitors, as this enables treatment of bleeding episodes with FVIII concentrates. However, since Immune Tolerance Induction (ITI) is a burdensome and costly treatment, it is important to identify determinants for ITI success to decide if it is worth undertaking ITI. For more effective treatment allocation, there is a need to identify which persons will or will not benefit from ITI. Aim: We aimed to identify determinants of successful ITI in PwSHA and to use these determinants in a clinical prediction model. Methods: German, Brazilian, Dutch, Canadian, and Italian PwSHA who underwent ITI were included. The primary outcome was clinical ITI success, defined by (1) a negative inhibitor titer, and (2) an adequate clinical response to FVIII concentrates. Clinical determinants included F8 genotype, race, age, cumulative exposure days to FVIII, inhibitor titers, and ITI regimen. Genetic determinants included in the analyses were FCGR gene, IL10 CA short tandem repeat, and gene variants. Crude Relative Risks (RR) were calculated for ITI success with 95% Confidence Intervals (95% CI). Results: In total, 224 PwSHA were included (61 German, 51 Brazilian, 45 Dutch, 39 Canadian, and 28 Italian). The median ages at inhibitor development and ITI start were 2-years (Interquartile Range [IQR 1‒3]) and 2-years (IQR 1‒6). The median interval between inhibitor diagnosis and ITI start was 17-weeks (IQR 2‒64). Most ITI trials started with recombinant FVIII (130; 58%) and the median prescribed regimen at ITI start was 43 IU/kg/day (IQR 21‒200). The need for adjuvant therapy and central venous access infection were related to failure, while inhibitor titer at detection < 10 BU/mL, inhibitor titer immediately before ITI start < 10 BU/mL, and peak inhibitor titer ever measured < 100 BU/mL were related to success. Inhibitor peak titer below 100 BU/mL showed the highest chance for ITI success (OR = 11.5, 95% CI 5.5‒24.3, p < 0.001). Conclusion: Historical peak titer below 100 BU/mL was the strongest determinant for ITI success. Genetic analyses will be available by the due date, and we will develop a prediction model to estimate the chance of success.

Clinical data on people with mild hemophilia (mPwH) is important to guide their treatment but remains scarce worldwide. In addition, since modern hemophilia therapies can turn severe phenotypes into mild or normal ones, knowing the clinical, therapeutical, and outcomes data of mPwH becomes essential as a proxy of these treatments. We described mPwH who participated in the 6th version of the Hemophilia in the Netherlands (HiN-6) cross-sectional nationwide study. Male mPwH (lowest plasmatic factor activity 5.1%‒40.0%) answered a questionnaire about their disease, treatment, and outcomes, in 2019. Questionnaires were elaborated according to age: younger than 12-years (children and responded by their parents/caregivers), between 12- and 17.9-years (adolescents), and 18-years or older (adults). A total of 387 mPwH responded to the questionnaires. Their median (Interquartile Range; IQR) age was 49.0-years (26.0‒62.0), 340 (87.8%) were adults, 29 (7.5%) had past or current inhibitors, 197 (50.9%) had ever been treated with any clotting product, and 12 (3.1%) were currently on prophylaxis. Approximately 74% reported they perceived their disease was not serious or not serious at all, and the different activity groups responded similarly. Recent bleed at any site was reported by 24/47 (51.1%) non-adults, related to the previous quarter, and 96/340 (28.2%) adults, related to the previous year. Joint impairment was reported for 180 joints (22 perceived as severe) by 50/387 (12.9%) mPwH. Age at first hemarthrosis was 10.0 years [5.0‒16.0] among 97 (25%) mPwH. Lifetime hospitalization due to joint surgery was reported by 31/358 (8.7%) mPwH. The analyses of PROMIS29 and RAND-26 (quality of life), and HAL (functional abilities) indicated good quality of life and functional abilities. mPwH who participated in the HiN-6 Study reported good social functioning and a non-impactant disease in their lives, although bleeds, joint impairment, and need for joint surgeries still occur.

Immune Tolerance Induction (ITI) is the only treatment to eradicate inhibitors in people with Severe Hemophilia A (SHA). Successful ITI restores Factor VIII (FVIII) tolerance. ITI is demanding and successful in approximately 70% of people. Therefore, identifying predictors of ITI outcome is essential to guide clinical decision-making. We aimed to identify genetic predictors of ITI success in people with SHA and inhibitors who underwent ITI. This observational multicenter study included people with SHA who underwent ITI, between 2015 and 2023. Clinical and patient data including factor VIII gene (F8) mutation type and DNA samples were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. The associations between ITI success and F8 genotype and 216 candidate predictors including single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA)-variants employing a global screening array (GSA), CA dinucleotide Short Tandem Repeat (STR) polymorphisms in the Interleukin (IL)-10 promoter region, and FCGR2/3 gene locus variations were analyzed. Of 204 participants, 147 (72.1%) achieved ITI success. The majority (52.0%) of participants had F8 intron 22 inversion. None of the candidate SNPs/HLA-variants, IL-10 CA dinucleotide STR, or FCGR2/3 gene locus variations were associated with ITI success. F8 large deletions were negatively associated with ITI success (OR = 0.15, 95% CI 0.04‒0.51, p = 0.002). Our study including 204 people with SHA identified F8 large deletions as a predictor of ITI failure. Pooling cohorts may allow the identification of additional genetic predictors of ITI success in the future.

Background: Inhibitor eradication to restore factor (F)VIII efficacy is the treatment goal for persons with severe hemophilia A (HA) and inhibitors. Immune tolerance induction (ITI) is demanding and successful in about 70% of people. Until now, it has remained difficult to quantify the probability of ITI success or failure, complicating the decision to initiate or not initiate ITI. Estimating the individual chance of ITI success allows clinicians, patients, and their families to support shared decision-making. Objectives: We aimed to identify clinical predictors of ITI success and to develop a clinical prediction model to estimate the chance of successful ITI in persons with severe HA. Methods: This multicenter study included persons with severe HA who received ITI. Clinical data were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. A multivariable logistic regression model was developed. Model performance and internal validation were performed. Results: Of 206 participants with a median age of 19.8 months (IQR, 12.1-38.8) at ITI start, 148 (71.8%) achieved ITI success. Our clinical prediction model included 4 predictors of ITI success: cumulative number of FVIII exposure days at inhibitor development, peak inhibitor titer, ethnicity, and F8 mutation type. The C statistic was 0.801 (95% CI, 0.70-0.87). Conclusion: In our study, including 206 people with severe HA and inhibitors, we developed a clinical prediction model to estimate the chance of successful ITI. After future external validation, this clinical prediction model may be useful for informing clinicians and families.

BackgroundTo enable personalized treatment and shared decision-making in chronic care, relevant health information is collected. However, health information is often fragmented across hospital information systems, digital health apps, and questionnaire portals. This also pertains to hemophilia care, in which scattered information hampers integrated care. We intend to co-design a nationwide digital personal health record (PHR) for patients to help manage their health information. For this, user perspectives are crucial. ObjectiveThis study aims to assess patients’ and health care providers’ perspectives regarding the use of a PHR in hemophilia care in the Netherlands, required functionalities, and expectations and concerns. MethodsIn this semistructured interview study, 19 pediatric and adult persons with hemophilia, parents, and women with other inherited bleeding disorders, as well as 18 health care providers working within and outside of hemophilia treatment centers, participated. Perspectives of patients and providers were explored separately. To explore requirements, participants were asked to prioritize functionalities. ResultsParticipants expected a PHR would increase the transparency of health information, improve patients’ understanding of their illness, and help the coordination of care between health care providers and institutions. Prioritized functionalities included the integration of relevant health information and patient-entered data. Formulated expectations and concerns focused on 4 themes: usability, safety, inclusiveness, and implementation. While patients expressed worries over medicalization (ie, more confrontational reminders of their illness), providers were concerned about an increased workload. ConclusionsPeople with hemophilia, their parents, and health care providers welcomed the development of a PHR, as they expected it would result in better coordinated care. Formulated expectations and concerns will contribute to the successful development of a PHR for persons with hemophilia, and ultimately, for all persons with a chronic condition.

For over 150 years, researchers have studied the (patho)physiology of the endocrine pancreas and devised treatment options for diabetes mellitus (DM). However, no cure has been developed so far. In dogs, diabetes mellitus type 1 (T1DM) is the most common presentation. Treatment consists of twice daily insulin injections, monitored by spatial blood glucose measurements. Even though dogs were instrumental in the discovery of insulin and islet transplantations, the treatment in diabetic dogs has remained unchanged for decades. Providing twice daily insulin injections is demanding for both owners and dogs and may result in hypoglycaemic events, creating the need for new treatment strategies. Novel regenerative medicine-based tools, such as improved β-cell culture protocols and artificial devices, have sparked hope for a cure. In human medicine, emerging technologies such as the transplantation of insulin-producing β-cells, generated by stem cell differentiation, with or without an encapsulation device, are currently tested in phase I/II clinical trials. As the pathogenesis of T1DM is remarkably similar between humans and dogs, novel treatment methods could be implemented in canine medicine. This review briefly summarises the physiology of the canine endocrine pancreas and the pathophysiology of canine DM before exploring current and possible future treatment options for canine DM.

Previous studies have demonstrated volatility-dependent absorption of gas-phase volatile organic compounds (VOCs) to Teflon and other polymers. Polymer–VOC interactions are relevant for atmospheric chemistry sampling, as gas–wall partitioning in polymer tubing can cause delays and biases during measurements. They are also relevant to the study of indoor chemistry, where polymer-based materials are abundant (e.g., carpets and paints). In this work, we quantify the absorptive capacities of multiple tubing materials, including four nonconductive polymers (important for gas sampling and indoor air quality), four electrically conductive polymers and two commercial steel coatings (for gas and particle sampling). We compare their performance to previously characterized materials. To quantify the absorptive capacities, we expose the tubing to a series of ketones in the volatility range 104–109 µg m−3 and monitor transmission. For slow-diffusion polymers (e.g., perfluoroalkoxy alkane (PFA) Teflon and nylon), absorption is limited to a thin surface layer, and a single-layer absorption model can fit the data well. For fast-diffusion polymers (e.g., polyethylene and conductive silicone), a larger depth of the polymer is available for diffusion, and a multilayer absorption model is needed. The multilayer model allows fitting solid-phase diffusion coefficients for different materials, which range from 4×10-9 to 4×10-7 cm2 s−1. These diffusion coefficients are ∼ 8 orders of magnitude larger than literature values for fluorinated ethylene propylene (FEP) Teflon film. This enormous difference explains the differences in VOC absorption measured here. We fit an equivalent absorptive mass (CW, µg m−3) for each absorptive material. We found PFA to be the least absorptive, with CW ∼ 105 µg m−3, and conductive silicone to be the most absorptive, with CW ∼ 1013 µg m−3. PFA transmits VOCs easily and intermediate-volatility species (IVOCs) with quantifiable delays. In contrast, conductive silicone tubing transmits only the most volatile VOCs, denuding all lower-volatility species. Semi-volatile species (SVOCs) are very difficult to sample quantitatively through any tubing material. We demonstrate a system combining several slow- and fast-diffusion tubing materials that can be used to separate a mixture of VOCs into volatility classes. New conductive silicone tubing contaminated the gas stream with siloxanes, but this effect was reduced 10 000-fold for aged tubing, while maintaining the same absorptive properties. SilcoNert (tested in this work) and Silonite (tested in previous work) steel coatings showed gas transmission that was almost as good as PFA, but since they undergo adsorption, their delay times may be humidity- and concentration-dependent.

Contemporary science and religion discourse (SRD) is a large field encompassing various topics, from creationism against evolution to theological anthropology and artificial intelligence, though historically, what is meant by “science” is Western science, and what is meant by “religion” is usually Christianity. Moreover, SRD has been driven mainly from the North American context. The scope of this paper will thus be more focused on Western science and North American Protestant Evangelical Christianity, which hereafter will be referred to as simply Christianity or religion. In this article, I argue that SRD often arises from conflict or intersections where such interdisciplinary dialogue is needed to better understand the topic. However, this also means that topics that seem to agree between religion and science are not discussed in SRD. It is as if the goal of SRD, consciously or unconsciously, is to attain some consensus. Topics that have achieved consensus are not worth interrogating using the interdisciplinary approach of SRD. In this article, I will raise the topic of the holy war on obesity as a case example. From the medical and scientific perspective, obesity is a significant epidemic and problem. Similarly, Christians also see obesity as a problem that their churches can help by reinforcing the need for self-control as a virtue. The alignment of the two fields leaves this subject primarily out of the radar of the academic SRD. Yet I argue here that this unholy alliance needs to be questioned because locating the solution to obesity simply on willpower to lose weight and battle gluttony is short-sighted at best, misleading perhaps, and harmful at worst. This paper calls for a transdisciplinary approach to the SRD on obesity, emphasizing the need to address the multifaceted nature of the problem, which spans physiology, psychology, sociology, economics, culture, and theology. In overlooking the complexity of the problem with its various intersectionalities, both science and religion in SRD have colonized bodies and health. Inherent within this transdisciplinary approach is the exercise of undisciplining SRD and decolonizing bodies. The concept of “undisciplining” involves re-evaluating the problem beyond mere weight loss, addressing interconnected issues such as food supply, government regulations, capitalism, discrimination, and mental health care. The narrative of gluttony as sin, the war metaphor, and the methodologies employed by both religious and scientific communities need to be deconstructed. In conclusion, recognizing the entangled system in which all are complicit, the paper advocates for a more nuanced and comprehensive approach, free from the constraints of traditional disciplinary boundaries and influenced narratives.

Abstract We previously observed lifelong endurance exercise (LLE) influenced quadriceps whole‐muscle and myofiber size in a fiber‐type and sex‐specific manner. The current follow‐up exploratory investigation examined myofiber size regulators and myofiber size distribution in vastus lateralis biopsies from these same LLE men (n = 21, 74 ± 1 years) and women (n = 7, 72 ± 2 years) as well as old, healthy nonexercisers (OH; men: n = 10, 75 ± 1 years; women: n = 10, 75 ± 1 years) and young exercisers (YE; men: n = 10, 25 ± 1 years; women: n = 10, 25 ± 1 years). LLE exercised ~5 days/week, ~7 h/week for the previous 52 ± 1 years. Slow (myosin heavy chain (MHC) I) and fast (MHC IIa) myofiber nuclei/fiber, myonuclear domain, satellite cells/fiber, and satellite cell density were not influenced (p > 0.05) by LLE in men and women. The aging groups had ~50%–60% higher proportion of large (>7000 μm2) and small (

Abstract Primary liver cancer arises either from hepatocytic or biliary lineage cells, giving rise to hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICCA). Combined hepatocellular- cholangiocarcinomas (cHCC-CCA) exhibit equivocal or mixed features of both, causing diagnostic uncertainty and difficulty in determining proper management. Here, we perform a comprehensive deep learning-based phenotyping of multiple cohorts of patients. We show that deep learning can reproduce the diagnosis of HCC vs. CCA with a high performance. We analyze a series of 405 cHCC-CCA patients and demonstrate that the model can reclassify the tumors as HCC or ICCA, and that the predictions are consistent with clinical outcomes, genetic alterations and in situ spatial gene expression profiling. This type of approach could improve treatment decisions and ultimately clinical outcome for patients with rare and biphenotypic cancers such as cHCC-CCA.

Volatile organic compound (VOC) emissions and subsequent oxidation contribute to the formation of secondary pollutants and poor air quality in general. As more VOCs at lower mixing ratios have become the target of air quality investigations, their quantification has been aided by technological advancements in proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS). However, such quantification requires appropriate instrument background measurements and calibrations, particularly for VOCs without calibration standards. This study utilized a Vocus PTR-TOF-MS coupled with a gas chromatograph for real-time and speciated measurements of ambient VOCs in Boulder, Colorado, during spring 2021. The aim of these measurements was to understand and characterize instrument response and temporal variability as to inform the quantification of a broader range of detected VOCs. Fast, frequent calibrations were made every 2 h in addition to daily multipoint calibrations. Sensitivities derived from the fast calibrations were 5 ± 6 % (average and 1 standard deviation) lower than those derived from the multipoint calibrations due to an offset between the calibrations and instrument background measurement. This offset was caused, in part, by incomplete mixing of the standard with diluent. These fast calibrations were used in place of a normalization correction to account for variability in instrument response and accounted for non-constant reactor conditions caused by a gradual obstruction of the sample inlet. One symptom of these non-constant conditions was a trend in fragmentation, although the greatest observed variability was 6 % (1 relative standard deviation) for isoprene. A PTR Data Toolkit (PTR-DT) was developed to assess instrument performance and rapidly estimate the sensitivities of VOCs which could not be directly calibrated on the timescale of the fast calibrations using the measured sensitivities of standards, molecular properties, and simple reaction kinetics. Through this toolkit, the standards' sensitivities were recreated within 1 ± 8 % of the measured values. Three clean-air sources were compared: a hydrocarbon trap, zero-grade air and ultra-high purity nitrogen, and a catalytic zero-air generator. The catalytic zero-air generator yielded the lowest instrument background signals for the majority of ions, followed by the hydrocarbon trap. Depending on the ionization efficiency, product ion fragmentation, ion transmission, and instrument background, standards' limits of detection (5 s measurement integration) derived from the catalytic zero-air generator and the fast calibration sensitivities ranged from 2 ppbv (methanol) to 1 pptv (decamethylcyclopentasiloxane; D5 siloxane) with most standards having detection limits below 20 pptv. Finally, applications of measurements with low detection limits are considered for a few low-signal species including sub-parts-per-trillion by volume (pptv) enhancements of icosanal (and isomers; 1 min average) in a plume of cooking emissions, and sub-parts-per-trillion by volume enhancements in dimethyl disulfide in plumes containing other organosulfur compounds. Additionally, chromatograms of hexamethylcyclotrisiloxane, octamethylcyclotetrasiloxane, and decamethylcyclopentasiloxane (D3, D4, and D5 siloxanes, respectively), combined with high sensitivity, suggest that online measurements can reasonably be associated with the individual isomers.

Abstract Background To enable successful inclusion of electroencephalography (EEG) outcome measures in Alzheimer’s disease (AD) clinical trials, we retrospectively mapped the progression of resting-state EEG measures over time in amyloid-positive patients with mild cognitive impairment (MCI) or dementia due to AD. Methods Resting-state 21-channel EEG was recorded in 148 amyloid-positive AD patients (MCI, n = 88; dementia due to AD, n = 60). Two or more EEG recordings were available for all subjects. We computed whole-brain and regional relative power (i.e., theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-13 Hz), beta (13-30 Hz)), peak frequency, signal variability (i.e., theta permutation entropy), and functional connectivity values (i.e., alpha and beta corrected amplitude envelope correlation, theta phase lag index, weighted symbolic mutual information, inverted joint permutation entropy). Whole-group linear mixed effects models were used to model the development of EEG measures over time. Group-wise analysis was performed to investigate potential differences in change trajectories between the MCI and dementia subgroups. Finally, we estimated the minimum sample size required to detect different treatment effects (i.e., 50% less deterioration, stabilization, or 50% improvement) on the development of EEG measures over time, in hypothetical clinical trials of 1- or 2-year duration. Results Whole-group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased beta power), with strongest effects for temporal and parieto-occipital regions. Disease severity at baseline influenced the EEG measures’ rates of change, with fastest deterioration reported in MCI patients. Only AD dementia patients displayed a significant decrease of the parieto-occipital peak frequency and theta signal variability over time. We estimate that 2-year trials, focusing on amyloid-positive MCI patients, require 36 subjects per arm (2 arms, 1:1 randomization, 80% power) to detect a stabilizing treatment effect on temporal relative theta power. Conclusions Resting-state EEG measures could facilitate early detection of treatment effects on neuronal function in AD patients. Their sensitivity depends on the region-of-interest and disease severity of the study population. Conventional spectral measures, particularly recorded from temporal regions, present sensitive AD treatment monitoring markers.

Background & Aims: In clinical practice, the diagnosis of alcohol-associated hepatitis (AH) is mostly based on non-invasive criteria, which were defined at a consensus conference by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). These criteria were recently modified by adding C-reactive protein (CRP) and termed NIAAAm-CRP criteria, which showed superior diagnostic accuracy for presence of alcohol-associated steatohepatitis (ASH) on liver histology. The aim of our study was to validate the diagnostic accuracy of both original NIAAA criteria and NIAAAm-CRP criteria for presence of ASH on liver histology in an independent cohort. Methods: Data from a large multinational cohort of 445 patients with alcohol-associated liver disease (ALD) that served to establish a novel grading and staging system of alcohol-associated liver disease were analyzed retrospectively. Diagnosis of ASH was based on presence of hepatocyte ballooning plus lobular neutrophil infiltration and established in virtual consensus meetings of multiple expert liver pathologists. Results: Complete data including CRP values were available in 346 patients. Overall diagnostic accuracy for prediction of ASH was 73% for NIAAA criteria and 77% for NIAAAm-CRP criteria. In a subgroup with suspected severe AH (MELD >20, n = 123), overall diagnostic accuracy for prediction of ASH was 69% for NIAAA criteria and 74% for NIAAAm-CRP criteria. Conclusion: Our findings confirm recent data on suboptimal diagnostic accuracy of original NIAAA criteria and validate slightly better but still suboptimal performance of NIAAAm-CRP criteria for presence of ASH. Impact and Implications: Alcohol-associated steatohepatitis (ASH) is diagnosed on liver histology but liver biopsy is not always feasible. Non-invasive diagnosis based on clinical findings has been proposed using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria and recently improved using NIAAAm-CRP criteria. Our findings validate slightly better but still suboptimal performance of NIAAAm-CRP criteria for the presence of histological ASH. Clinical trials of novel drugs should focus on histologically proven ASH.