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IntroductionProstate multiparametric magnetic resonance imaging (mpMRI) has greatly improved the detection of clinically significant prostate cancer (csPCa). However, the limited number of expert sub-specialist radiologists capable of interpreting conventional prostate mpMRI is a bottleneck for universal access to this healthcare advance. A reliable and reproducible quantitative imaging biomarker could facilitate implementation of accurate prostate MRI at clinical sites with limited experience, thus ensuring more equitable patient care. Restriction Spectrum Imaging restriction score (RSIrs) is an MRI biomarker that has shown the ability to enhance the qualitative and quantitative interpretation of prostate MRI. However, patient-level factors (age, race, ethnicity, prostate volume, and 5-alpha-reductase inhibitor (5-ARI) use) and acquisition-level factors (scanner manufacturer/model and protocol parameters) can affect prostate mpMRI, and their impact on quantitative RSIrs is unknown.MethodsRSI data from patients with known or suspected csPCa were collected from seven centers. We estimated effects of patient and acquisition factors on prostate voxels overall (Method 1: benign patients only) and on only the maximum RSIrs within each prostate (RSIrsmax; Method 2: benign and csPCa patients) using linear models. We then tested whether adjusting for any estimated systematic biases would improve performance of RSIrs for patient-level detection of csPCa, as measured by area under the ROC curve (AUC).ResultsUsing both Method 1 and Method 2, we observed statistically significant effects on RSIrs of age and acquisition group (p < 0.05). Prostate volume had significant effects using only Method 2. All of these effects were small, and adjusting for them did not improve csPCa detection performance (p ≥ 0.05). AUC of RSIrsmaxfor patient-level csPCa detection was 0.77 (95% CI: 0.75, 0.79) unadjusted, compared to 0.77 (0.76, 0.79) and 0.74 (0.72, 0.76) after adjustment using Method 1 and 2 respectively.ConclusionAge, prostate volume, and imaging acquisition factors may lead to systematic differences in RSIrs, but these effects are small and have minimal impact on performance of RSIrs for detection of csPCa. RSIrs can be used as a reliable biomarker across a wide range of patients, centers, scanners, and acquisition factors.

Abstract: Background: Multiparametric MRI (mpMRI) is strongly recommended by current clinical guidelines for improved detection of clinically significant prostate cancer (csPCa). However, major limitations of mpMRI are the need for intravenous (IV) contrast and dependence on reader expertise. Efforts to address these issues include use of biparametric MRI (bpMRI) and advanced, quantitative MRI techniques. One such advanced technique is the Restriction Spectrum Imaging restriction score (RSIrs), an imaging biomarker that has been shown to improve quantitative accuracy of patient-level csPCa detection. Purpose: To evaluate whether IV contrast can be avoided in the setting of standardized, state-of-the-art image acquisition, with or without addition of RSIrs, and to evaluate characteristics of RSIrs as a stand-alone, quantitative biomarker. Design, setting, and participants: ART-Pro is a multisite, multinational trial that will be conducted in two stages, evaluating bpMRI, mpMRI, and RSIrs on accuracy of expert (ART-Pro-1) and non-expert (ART-Pro-2) radiologists’ detection of csPCa. Additionally, RSIrs will be evaluated as a stand-alone, quantitative, objective biomarker (ART-Pro-1). This study will include a total of 500 patients referred for a multiparametric prostate MRI with a clinical suspicion of prostate cancer at any of the five participating sites (100 patients per site). Intervention: In ART-Pro-1, patients receive standard of care mpMRI, with addition of the RSI sequence, and subsets of the patients’ images are read separately by two expert radiologists, one of whom is the standard of care radiologist (Reader 1). Three research reports are generated using: bpMRI only (Reader 1), mpMRI (Reader 1), and bpMRI + RSIrs (Reader 2). The clinical report is submitted by Reader 1. Patients’ future prostate cancer management will be recorded and used to evaluate the performance of the MRI techniques being tested. In ART-Pro-2, the dataset created in ART-Pro-1 will be retrospectively reviewed by radiologists of varying experience level (novice, basic, and expert). Radiologists will be assigned to read cases and record research reports while viewing subsets of either mpMRI only or RSIrs + mpMRI. Patient cases will be read by two readers from each experience level (6 reads total), and findings will be evaluated against the expertly created dataset from ART-Pro-1. Outcome measurements and statistical analysis: The primary endpoint is to evaluate if bpMRI is non-inferior to mpMRI among expert radiologists (ART-Pro-1) and non-expert radiologists (ART-Pro-2) for detection of grade group (GG) ≥2 csPCa. We will conduct one-sided non-inferiority tests of correlated proportions (ART-Pro-1) and use McNemar’s test and AUC to test the null hypothesis of non-inferiority (ART-Pro-1 and ART-Pro-2). Conclusions: This trial is registered in the US National Library of Medicine Trial Registry (NCT number:NCT06579417) atClinicalTrials.gov. Patient accrual at the first site (UC San Diego) began in December 2023. The expected trial timeline is three years to complete accrual with a six-month endpoint.

Abstract: Background and Objective: Positive predictive value of PI-RADS for clinically significant prostate cancer (csPCa, grade group [GG]≥2) varies widely between institutions and radiologists. The Restriction Spectrum Imaging restriction score (RSIrs) is a metric derived from diffusion MRI that could be an objectively interpretable biomarker for csPCa. Methods: In patients scanned for suspected or known csPCa at 7 centers, we calculated patient-level csPCa probability based on maximum RSIrs in the prostate, without relying on subjectively defined lesions. We used area under the ROC curve (AUC) to compare patient-level csPCa detection for RSIrs, ADC, and PI-RADS. Finally, we combined RSIrs with clinical risk factors via multivariable regression, training in a single-center cohort and testing in an independent, multi-center dataset. Key Findings and Limitations: Among all patients (n=1892), probability of csPCa increased with higher RSIrs . GG≥4 csPCa was most common in patients with very high RSIrs. Among biopsy-naïve patients (n=877), AUCs for GG≥2 vs. non-csPCa were 0.73 (0.69-0.76), 0.54 (0.50-0.57), and 0.75 (0.71-0.78) for RSIrs, ADC, and PI-RADS, respectively. RSIrs significantly outperformed ADC (p

Abstract Habitual consumption of low-calorie sweeteners (LCS) during juvenile-adolescence can lead to greater sugar intake later in life. Here, we investigated if exposure to the LCS Acesulfame Potassium (Ace-K) during this critical period of development reprograms the taste system in a way that would alter hedonic responding for common dietary compounds. Results revealed that early-life LCS intake not only enhanced the avidity for a caloric sugar (fructose) when rats were in a state of caloric need, it increased acceptance of a bitterant (quinine) in Ace-K-exposed rats tested when middle-aged. These behavior shifts, which endured months after the end of Ace-K exposure, were accompanied by widespread changes in the peripheral taste system. The anterior tongue had fewer fungiform taste papillae, and the circumvallate papillae had a reduced anterior to posterior span and diminished expression of genes involved in sweet reception, sweet and bitter intracellular signaling, fructose transport, and cellular progeneration in the Ace-K-exposed rats. Ace-K exposure also led to a significant reduction in dopamine-producing cells of the ventral tegmental area. The collective findings reveal that LCS intake early in life alters the taste-brain axis and the behavioral responsiveness to both positive and negative tastants that are important determinants of dietary preferences.

Multiparametric magnetic resonance imaging (mpMRI) is strongly recommended by current clinical guidelines for improved detection of clinically significant prostate cancer (csPCa). However, the major limitations are the need for intravenous (IV) contrast and dependence on reader expertise. Efforts to address these issues include use of biparametric magnetic resonance imaging (bpMRI) and advanced, quantitative magnetic resonance imaging (MRI) techniques. One such advanced technique is the Restriction Spectrum Imaging restriction score (RSIrs), an imaging biomarker that has been shown to improve quantitative accuracy of patient-level csPCa detection. Advanced Restriction imaging and reconstruction Technology for Prostate MRI (ART-Pro) is a multisite, multinational trial that aims to evaluate whether IV contrast can be avoided in the setting of standardized, state-of-the-art image acquisition, with or without addition of RSIrs. Additionally, RSIrs will be evaluated as a stand-alone, quantitative, objective biomarker. ART-Pro will be conducted in two stages and will include a total of 500 patients referred for multiparametric prostate MRI with a clinical suspicion of prostate cancer at the participating sites. ART-Pro-1 will evaluate bpMRI, mpMRI, and RSIrs on the accuracy of expert radiologists’ detection of csPCa and will evaluate RSIrs as a stand-alone, quantitative, objective biomarker. ART-Pro-2 will evaluate the same MRI techniques on the accuracy of nonexpert radiologists’ detection of csPCa, and findings will be evaluated against the expertly created dataset from ART-Pro-1. The primary endpoint is to evaluate whether bpMRI is noninferior to mpMRI among expert (ART-Pro-1) and nonexpert (ART-Pro-2) radiologists for the detection of grade group ≥2 csPCa. This trial is registered in the US National Library of Medicine Trial Registry (NCT number: NCT06579417) at ClinicalTrials.gov. Patient accrual at the first site (UC San Diego) began in December 2023. Initial results are anticipated by the end of 2026.

Abstract Asthma affects approximately 300 million individuals worldwide and the onset predominantly arises in childhood. Children are exposed to multiple environmental irritants, such as viruses and allergens, that are common triggers for asthma onset, whilst their immune systems are developing in early life. Understanding the impact of allergen exposures on the developing immune system and resulting alterations in lung function in early life will help prevent the onset and progression of allergic asthma in children. In this study, we developed an in silico model describing the pulmonary immune response to a common allergen, house dust mite, to investigate its downstream impact on the pathophysiology of asthma, including airway eosinophilic inflammation, remodelling, and lung function. We hypothesised that altered epithelial function following allergen exposure determines the onset of airway remodelling and abnormal lung function, which are irreversible with current asthma therapies. We calibrated the in silico model using age appropriate in vivo data from neonatal and adult mice. We validated the in silico model using in vivo data from mice on the effects of current treatment strategies. The in silico model recapitulates experimental observations and provides an interpretable in silico tool to assess airway pathology and the underlying immune responses upon allergen exposure. The in silico model simulations predict the extent of bronchial epithelial barrier damage observed when allergen sensitisation occurs and demonstrate that epithelial barrier damage and impaired immune maturation are critical determinants of reduced lung function and asthma development. The in silico model demonstrates that both epithelial barrier repair and immune maturation are potential targets for therapeutic intervention to achieve successful asthma prevention.

Most students acknowledge shared responsibility, with the university, for their employability development. Many academics use assessments as the main driver for motivating students to learn. At the intersection between employability, assessment and learning, the emergent research question is -- what are the mechanisms by which course-based employability is fostered? Prior research reveals that although academics identified course-based assessment as the key employability mechanism, neither students nor employers registered this conceptualisation, and thus purpose of assessment. The aim of this research was to stimulate and communicate the direct connection between assessment and employability to students and interpret their response. Over 100 first-year students, across a metropolitan and regional Australian university, participated. Students were directed to use a simple reflective tool, dubbed iASK by the researchers, that probed employability elements of identity, Attributes, Skills, and Knowledge. The research revealed the resulting student view that regular course-based assessment can develop their employability skills in communication and independence, but not in critical thinking and global citizenship.

The NASA Atmospheric Tomography (ATom) mission built a photochemical climatology of air parcels based on in situ measurements with the NASA DC-8 aircraft along objectively planned profiling transects through the middle of the Pacific and Atlantic oceans. In this paper we present and analyze a data set of 10s (2km) merged and gap-filled observations of the key reactive species driving the chemical budgets of O3 and CH4 (O3, CH4, CO, H2O, HCHO, H2O2, CH3OOH, C2H6, higher alkanes, alkenes, aromatics, NOx, HNO3, HNO4, peroxyacetyl nitrate, and other organic nitrates), consisting of 146494 distinct air parcels from ATom deployments 1 through 4. Six models calculated the O3 and CH4 photochemical tendencies from this modeling data stream for ATom 1. We find that 80%-90% of the total reactivity lies in the top 50% of the parcels and 25%-35% in the top 10%, supporting previous model-only studies that tropospheric chemistry is driven by a fraction of all the air. Surprisingly, the probability densities of species and reactivities averaged on a model scale (100 km) differ only slightly from the 2km ATom 10s data, indicating that much of the heterogeneity in tropospheric chemistry can be captured with current global chemistry models. Comparing the ATom reactivities over the tropical oceans with climatological statistics from six global chemistry models, we find generally good agreement with the reactivity rates for O3 and CH4. Models distinctly underestimate O3 production below 2km relative to the mid-troposphere, and this can be traced to lower NOx levels than observed. Attaching photochemical reactivities to measurements of chemical species allows for a richer, yet more constrained-to-what-matters, set of metrics for model evaluation. This paper presents a corrected version of the paper published under the same authors and title (sans "corrected") as 10.5194/acp-21-13729-2021.

Abstract Pregnancy represents a period of immense maternal physiological adaptation, with progressive increases in lipid storage potential and insulin resistance to support fetal/placental growth. This requires significant change in the adipose tissue. Women living with obesity/overweight are more susceptible to these changes causing complications such as gestational diabetes. This is particularly worrying as up to 60% of European women are living with overweight/obesity at the onset of pregnancy. Furthermore, less than 1% meet all nutrition guidelines. There is now evidence that these deep metabolic changes can result in a predisposition to metabolic disease in both the mother and child in later life. Health and nutrition status during this period therefore represents a window to future health. This period offers a valuable opportunity for intervention to prevent the negative consequences of poor in utero environments and increases the long‐term quality of life for mother and offspring. This review will examine a range of in utero factors which determine adipose tissue development, the impact of these factors on later‐life obesity and metabolic health and the therapeutic value of dietary anti‐inflammatory nutritional interventions during pregnancy and early life. When it comes to early life nutrition, a ‘one size fits all’ approach is not always appropriate. Understanding the mechanisms of adipose tissue development in response to differing nutritional strategies may be important in the context of complicated or adverse in utero environments and represents a substantial step towards a more personalised nutritional approach for the prevention of obesity, metabolic syndrome and related non‐communicable diseases in future generations.

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

Summary: Leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme, with dual activities critical in defining the scale of tissue inflammation and pathology. LTA4H classically operates intracellularly, primarily within myeloid cells, to generate pro-inflammatory leukotriene B4. However, LTA4H also operates extracellularly to degrade the bioactive collagen fragment proline-glycine-proline to limit neutrophilic inflammation and pathological tissue remodeling. While the dichotomous functions of LTA4H are dictated by location, the cellular source of extracellular enzyme remains unknown. We demonstrate that airway extracellular LTA4H concentrations are governed by the level of pulmonary vascular permeability and influx of an abundant repository of blood-borne enzyme. In turn, blood LTA4H originates from liver hepatocytes, being released constitutively but further upregulated during an acute phase response. These findings have implications for our understanding of how inflammation and repair are regulated and how perturbations to the LTA4H axis may manifest in pathologies of chronic diseases.

BackgroundMen with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer.MethodsIn this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting.FindingsBetween May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths.Interpretation24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term.FundingInsightec and the National Cancer Institute.

The mammalian airways and lungs are exposed to a myriad of inhaled particulate matter, allergens, and pathogens. The immune system plays an essential role in protecting the host from respiratory pathogens, but a dysregulated immune response during respiratory infection can impair pathogen clearance and lead to immunopathology. Furthermore, inappropriate immunity to inhaled antigens can lead to pulmonary diseases. A complex network of epithelial, neural, stromal, and immune cells has evolved to sense and respond to inhaled antigens, including the decision to promote tolerance versus a rapid, robust, and targeted immune response. Although there has been great progress in understanding the mechanisms governing immunity to respiratory pathogens and aeroantigens, we are only beginning to develop an integrated understanding of the cellular networks governing tissue immunity within the lungs and how it changes after inflammation and over the human life course. An integrated model of airway and lung immunity will be necessary to improve mucosal vaccine design as well as prevent and treat acute and chronic inflammatory pulmonary diseases. Given the importance of immunology in pulmonary research, the American Thoracic Society convened a working group to highlight central areas of investigation to advance the science of lung immunology and improve human health.

Early childhood education (ECE) settings play a crucial role in promoting physical and social development among children aged 3–7 years. This systematic review sought to examine the associations between characteristics of ECE outdoor environments, social interactions, physical activity, and motor competence. The secondary aim examines previously applied methods to capture children’s behaviour in the context of their social and physical environment. Methods: This review used the PRISMA framework and study quality was assessed using the mixed-methods appraisal tool (MMAT). Keyword searches were conducted in seven databases. Studies were eligible if children were aged 3–7 years in ECE; physical activity, social interactions and/or motor competence were measured; location and/or social context were measured. Results were synthesised using an effect direct plot, a table of associations, and narrative synthesis. Results: Twenty-three studies from eight countries met the inclusion criteria. Intervention and controlled cross-sectional studies (n = 9) favoured high-quality outdoor environments rich in affordances, portable play equipment, and natural features to increase children’s physical activity, social interactions, and cooperative play. Cross-sectional and descriptive studies (n = 14) positively associated open grassy space, portable and fixed equipment, wheeled toys, and paths with physical activity (p < 0.05). Based on limited evidence, playground size and active games in small groups were associated with greater MC. Conclusions: The findings highlight the benefit of creating diverse affordance rich outdoor environments in early childhood settings to promote physical and social development. Limitations include variability in study designs and protocols for conducting systematic observations, thus emphasising the need for standardised approaches to future research.

Background: Physical literacy (PL) is increasingly recognised as essential for fostering lifelong engagement in physical activity (PA), particularly when nurtured in early childhood. Yet there remains limited understanding of how stakeholders in early years (EY) education perceive, value, and implement a PL-informed approach. This study aims to explore knowledge and beliefs regarding PL and PA in relation to 3–5-year-olds, investigating key questions around perceived importance, current practices, and barriers to implementation. Methods: A concurrent mixed-methods approach was used, incorporating semi-structured expert interviews (n = 11), focus groups (n = 22), and a survey (n = 210). Thematic analysis was used to identify key themes from qualitative data, and survey data were analysed to complement and triangulate the qualitative findings. Results: The findings revealed variation in stakeholders’ awareness of PA recommendations and confusion over terminology. Whilst stakeholders acknowledged the importance of PL, there remains uncertainty about the connection between theory and practical application. Identified barriers included resource limitations, conflicting priorities, and insufficient training and policy support. Feedback on an educational PL-EY model was generally positive, suggesting strong potential as a tool to support PL understanding and application in early childhood contexts. Conclusions: Given the pivotal role of EY education in shaping children’s behaviours, health, and wellbeing, this study highlights the necessity of a holistic approach to interventions, strong stakeholder involvement, and evidence-based practices to foster PL in EY children. The PL-EY model presents a promising direction for future resources and education and raises critical questions about what effective interventions to develop PL in this age group should consider and look like.

This paper reports on the development and piloting of a new model of multiplechoice question (MCQ) assessment used in two undergraduate degree modules at a tertiary university. The new model was purposefully designed to promote deeper learning closely aligned with the SOLO taxonomy. Students were invited to participate in an exploratory qualitative study exploring their experience of learning using this new assessment. In total, 13 students completed an online open-ended qualitative questionnaire. Data was analyzed thematically. Four themes were generated: (a) empowered choice, (b) iterative reading, (c) forcing comparison, and (d) justified understandings. Findings suggest that the new model MCQ assessment promoted wider and more prolonged engagement with learning materials and fostered critical comparisons resulting in deeper learning. Limitations in study design mean that further research is merited to develop our model of MCQ assessment and enhance our understanding of students' learning experience.

We present the first systematic inventory of surge-type glaciers for the whole of Greenland compiled from published datasets and multitemporal satellite images and digital elevation models. The inventory allows us to define the spatial and climatic distribution of surge-type glaciers and to analyse the timing of surges from 1985 to 2019. We identified 274 surge-type glaciers, an increase of 37% compared to previous work. Mapping surge-type glacier distribution by temperature and precipitation variables derived from ERA5-Land reanalysis data shows that the west and east clusters occur in well-defined climatic envelopes. Analysis of the timing of surge active phases during the periods ~1985 to 2000 (T1) and ~2000 to 2019 (T2) suggests that overall surge activity is similar in T1 and T2, but there appears to be a reduction in surging in the west cluster in T2. Our climate analysis shows a coincident increase in mean annual and mean winter air temperature between T1 and T2. We suggest that as glaciers thin under current warming, some surge-type glaciers in the west cluster may be being prevented from surging due to (1) their inability to build-up sufficient mass and (2) a switch from a polythermal to a largely cold-based thermal regime.

Abstract Background People with human immunodeficiency virus have an increased risk of developing AIDS-defining malignancies including Burkitt lymphoma. Survival outcomes in HIV-associated Burkitt lymphoma remain worse than non-HIV-associated Burkitt lymphoma, despite widespread implementation of antiretroviral therapy. We aimed to determine the association between HIV status and risk for 30-day and 90-day readmission in the US after index hospitalization for Burkitt lymphoma. Methods Data were abstracted from the 2010–2020 Nationwide Readmissions Database; hospitalizations included patients with a primary BL diagnosis and were stratified by comorbid HIV. The primary outcome was all-cause readmission (30-day and 90-day). Secondary outcomes were in-hospital mortality, length of stay (LOS), and hospital cost. Between-HIV differences were evaluated via logistic and log-normal regression; multivariable models adjusted for comorbid kidney disease, hypertension, fluid and electrolyte disorders, and sepsis. Results Overall, there were 8,453 hospitalizations for BL and 6.0% carried an HIV diagnosis. Of BL hospitalizations, 68.4% were readmitted within 30-days post index BL hospitalization and 6.8% carried a HIV diagnosis. HIV-associated BL was associated with 43% higher adjusted odds of 30-day readmission (aOR 95% CI: 4% higher to 97% higher, p = 0.026). For 90-day readmission, 76.0% of BL patients were readmitted and 7.0% carried a HIV diagnosis. HIV-associated BL was not statistically associated with all-cause 90-day readmission (aOR 1.46, aOR 95% CI: 0% higher to 115% higher, p = 0.053). Conclusions HIV-positive status is associated with an increased risk for 30-day readmission after index hospitalization for Burkitt lymphoma.

Abstract Breast cancer leptomeningeal metastasis (BCLM), where tumour cells grow along the lining of the brain and spinal cord, is a devastating development for patients. Investigating this metastatic site is hampered by difficulty in accessing tumour material. Here, we utilise cerebrospinal fluid (CSF) cell-free DNA (cfDNA) and CSF disseminated tumour cells (DTCs) to explore the clonal evolution of BCLM and heterogeneity between leptomeningeal and extracranial metastatic sites. Somatic alterations with potential therapeutic actionability were detected in 81% (17/21) of BCLM cases, with 19% detectable in CSF cfDNA only. BCLM was enriched in genomic aberrations in adherens junction and cytoskeletal genes, revealing a lobular-like breast cancer phenotype. CSF DTCs were cultured in 3D to establish BCLM patient-derived organoids, and used for the successful generation of BCLM in vivo models. These data reveal that BCLM possess a unique genomic aberration profile and highlight potential cellular dependencies in this hard-to-treat form of metastatic disease.

Abstract Background Infectious bovine keratoconjunctivitis (IBK) is a common cause of morbidity in cattle, resulting in significant economic losses. This study aimed to characterize the bovine bacterial ocular surface microbiome (OSM) through conjunctival swab samples from Normal eyes and eyes with naturally acquired, active IBK across populations of cattle using a three-part approach, including bacterial culture, relative abundance (RA, 16 S rRNA gene sequencing), and semi-quantitative random forest modeling (real-time polymerase chain reaction (RT-PCR)). Results Conjunctival swab samples were obtained from eyes individually classified as Normal (n = 376) or IBK (n = 228) based on clinical signs. Cattle unaffected by IBK and the unaffected eye in cattle with contralateral IBK were used to obtain Normal eye samples. Moraxella bovis was cultured from similar proportions of IBK (7/228, 3.07%) and Normal eyes (1/159, 0.63%) (p = 0.1481). Moraxella bovoculi was cultured more frequently (p 0.05). Alpha-diversity indices for geographic location (p

ABSTRACT Common bean (Phaseolus vulgaris L.) is a grain legume rich in proteins and micronutrients, particularly iron and zinc. In this study, 30 small‐seeded genotypes were planted in five locations in Ethiopia, following an alpha lattice design with three replications, to determine environmental and genotypic influence on the Fe and Zn concentration. Based on their Fe and Zn contents, bean cultivars were evaluated for adaptability and stability using AMMI analysis. The Fe concentrations of raw bean seed varied from 44.4 to 84.4 μg/g within the panel of small‐seeded genotypes, with an average range of variance of 18 μg/g across environments, and its seed Zn concentrations varied from 19.7 to 32.3 μg/g, with an average range of variance of 12.6 μg/g across environments. The averages bean Fe concentration among the small‐seeded genotypes across sites in Ethiopia was 62.2 and 26.1 μg/g for Zn concentrations. Results from the analysis of variance using the AMMI model indicated that genotypes accounted for 20.53% and 9.49% of the total variance in seed Fe and Zn concentrations, respectively. The environment had a greater impact, affecting 60.92% and 81.52% of total sum of squares for Fe and Zn concentrations, respectively. According to the broad‐sense heritability, there appears to be some genetic control over Fe and Zn concentrations. However, the substantial effects of the environment and genotype‐by‐environment interaction on Fe and Zn concentrations in small‐seeded genotypes indicates breeding for higher amounts of trace minerals in new bean varieties could be a challenging task. This means the notion that beans can be biofortified to have higher concentrations of Fe and Zn might not be achievable in Ethiopia. A shift in breeding strategies that focuses on traits to enhance the bioavailability of Fe and Zn from bean is warranted and could be a solution to enhance the delivery of iron from small‐seeded beans produced in Ethiopia.

Abstract Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry- based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.

Abstract Diabetes mellitus increases risk for tuberculosis disease and adverse outcomes. Most people with both conditions have type 2 diabetes, but it is unknown if type 1 and type 2 diabetes have identical effects on tuberculosis susceptibility. Here we show that male mice receiving a high-fat diet and streptozotocin to model type 2 diabetes, have higher mortality, more lung pathology, and higher bacterial burden following Mycobacterium tuberculosis infection compared to mice treated with streptozotocin or high-fat diet alone. Type 2 diabetes model mice have elevated plasma glycerol, which is a preferred carbon source for M. tuberculosis. Infection studies with glycerol kinase mutant M. tuberculosis reveal that glycerol utilization contributes to the susceptibility of the type 2 diabetes mice. Hyperglycemia impairs protective immunity against M. tuberculosis in both forms of diabetes, but our data show that elevated glycerol contributes to an additional adverse effect uniquely relevant to type 2 diabetes.

Abstract Rationale and objectives The study aims to propose an optimal workflow in patients with a PI‐RADS 3 (PR‐3) assessment category (AC) through determining the timing and type of pathology interrogation used for the detection of clinically significant prostate cancer (csPCa) in these men based upon a 5‐year retrospective review in a large academic medical center. Materials and methods This United States Health Insurance Probability and Accountability Act (HIPAA)‐compliant, institutional review board‐approved retrospective study included men without prior csPCa diagnosis who received PR‐3 AC on magnetic resonance (MR) imaging (MRI). Subsequent incidence and time to csPCa diagnosis and number/type of prostate interventions was recorded. Categorical data were compared using Fisher's exact test and continuous data using ANOVA omnibus F‐test. Results Our cohort of 3238 men identified 332 who received PR‐3 as their highest AC on MRI, 240 (72.3%) of whom had pathology follow‐up within 5 years. csPCa was detected in 76/240 (32%) and non‐csPCa in 109/240 (45%) within 9.0 ± 10.6 months. Using a non‐targeted trans‐rectal ultrasound biopsy as the initial approach (n = 55), another diagnostic procedure was required to diagnose csPCa in 42/55 (76.4%) of men, compared with 3/21(14.3%) men with an initial MR targeted‐biopsy approach (n = 21); (p

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

Background: Childhood obesity is a significant public health crisis that is exposing children to associated morbidities and premature mortality. However, parents can positively influence physical activity trajectories and improve health outcomes by nurturing fundamental movement skills (FMS) in children. This is the first study to explore the determinants of family FMS practice via a systematic synthesis of qualitative evidence. Methods: Keyword searches were completed in SPORTDiscus, PubMed, Scopus, Web of Science, and Embase. Studies that offered perspectives relating to influences on the FMS of 2–6-year-old children in the family context via qualitative approaches, including visual methodologies that provided an important voice to children, were included. A thematic analysis was used to establish key themes. Results: The emergent themes included parent knowledge and beliefs, self-efficacy of parents to teach, and the home environment. Parents often undervalued FMS and lacked the self-efficacy to teach due to poor understanding, conflicting priorities, and multifaceted societal influences. Children preferred autonomous play and socialisation but were negatively influenced by technology and restrictive household rules. Conclusions: Greater knowledge exchange between stakeholders is necessary to empower parents and enhance FMS application at home. More community initiatives could facilitate greater access to outdoor spaces, facilities, and equipment, which may improve family engagement with FMS.

IntroductionWhile the relationship between narcissism and empathy has been well-researched, studies have paid less attention to empathic accuracy, i.e., appreciating the precise strength of another person’s emotions, and self-other distinction, in terms of the disparity between affective ratings for self and other in response to emotive stimuli. Furthermore, empathic responses may vary depending on whether the pain is physical or social.MethodsWe investigated empathic accuracy, affective empathy, and the distinction between pain, emotion and intensity ratings for self and other, in high (n = 44) and low (n = 43) narcissism groups (HNG and LNG, respectively) selected from 611 students, in response to both types of pain. Participants watched six videos where targets expressed genuine experiences of physical and social pain, and rated the perceived affect and pain experienced by the person in the video and their own empathic emotional responses.Results and discussionThe HNG displayed lower affective empathy and empathic accuracy than the LNG for both pain types. Within the HNG there was higher empathic accuracy for social vs. physical pain, despite reduced affective empathy for social pain, in contrast to the LNG. In addition to this paradox, the HNG demonstrated greater differences between ratings for the self and for target others than the LNG, suggesting that narcissism is associated with higher self-other distinction in response to viewing other people describing social pain.

Background Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice.Methods We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4+/CD8+ ratio), activity in vitro against endosialin+ and endosialin– cells, and expansion and activity in vivo in syngeneic tumor models as well as in tumor-naive healthy and wounded mice and tumor-bearing endosialin knockout mice was assessed.Results E3K CAR-T cells were active in vitro against both mouse and human endosialin+, but not endosialin–, cells. Adoptively transferred E3K CAR-T cells exhibited no activity in endosialin knockout mice, tumor-naive endosialin wildtype mice or in wound healing models, demonstrating an absence of off-target and on-target/off-tumor activity. By contrast, adoptive transfer of E3K CAR-T cells into BALB/c, FVB/N or C57BL/6 mice bearing syngeneic breast or lung cancer lines depleted target cells in the tumor stroma resulting in increased tumor necrosis, reduced tumor growth and a substantial impairment in metastatic outgrowth.Conclusions Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin+ cells makes a humanized and optimized E3K CAR a promising candidate for clinical development applicable to a broad range of solid tumor types.

The NASA Atmospheric Tomography (ATom) mission built a photochemical climatology of air parcels based on in situ measurements with the NASA DC-8 aircraft along objectively planned profiling transects through the middle of the Pacific and Atlantic oceans. In this paper we present and analyze a data set of 10s (2km) merged and gap-filled observations of the key reactive species driving the chemical budgets of O3 and CH4 (O3, CH4, CO, H2O, HCHO, H2O2, CH3OOH, C2H6, higher alkanes, alkenes, aromatics, NOx, HNO3, HNO4, peroxyacetyl nitrate, other organic nitrates), consisting of 146494 distinct air parcels from ATom deployments 1 through 4. Six models calculated the O3 and CH4 photochemical tendencies from this modeling data stream for ATom 1. We find that 80%-90% of the total reactivity lies in the top 50% of the parcels and 25%-35% in the top 10%, supporting previous model-only studies that tropospheric chemistry is driven by a fraction of all the air. In other words, accurate simulation of the least reactive 50% of the troposphere is unimportant for global budgets. Surprisingly, the probability densities of species and reactivities averaged on a model scale (100km) differ only slightly from the 2km ATom data, indicating that much of the heterogeneity in tropospheric chemistry can be captured with current global chemistry models. Comparing the ATom reactivities over the tropical oceans with climatological statistics from six global chemistry models, we find excellent agreement with the loss of O3 and CH4 but sharp disagreement with production of O3. The models sharply underestimate O3 production below 4km in both Pacific and Atlantic basins, and this can be traced to lower NOx levels than observed. Attaching photochemical reactivities to measurements of chemical species allows for a richer, yet more constrained-to-what-matters, set of metrics for model evaluation.

The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well-annotated genome, wealth of genetic resources, and the ability to precisely manipulate its genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost-effective, informative, and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole-genome sequencing. Here, we describe the content and performance of a new iteration of the Mouse Universal Genotyping Array (MUGA), MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: (1) chromosomal sex determination, (2) discrimination between substrains from multiple commercial vendors, (3) diagnostic SNPs for popular laboratory strains, (4) detection of constructs used in genetically engineered mice, and (5) an easy-to-interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA, we genotyped 6899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays, both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived, and recombinant inbred lines. Here, we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, new markers that expand the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. We provide preliminary evidence that the array can be used to identify both partial sex chromosome duplication and mosaicism, and that diagnostic SNPs can be used to determine how long inbred mice have been bred independently from the relevant main stock. We conclude that MiniMUGA is a valuable platform for genetic QC, and an important new tool to increase the rigor and reproducibility of mouse research.

The prenatal and perinatal environments can have profound effects on the development of chronic inflammatory diseases. However, mechanistic insight into how the early-life microenvironment can impact upon development of the lung and immune system and consequent initiation and progression of respiratory diseases is still emerging. Recent studies investigating the developmental origins of lung diseases have started to delineate the effects of early-life changes in the lung, environmental exposures and immune maturation on the development of childhood and adult lung diseases. While the influencing factors have been described and studied in mostly animal models, it remains challenging to pinpoint exactly which factors and at which time point are detrimental in lung development leading to respiratory disease later in life. To advance our understanding of early origins of chronic lung disease and to allow for proper dissemination and application of this knowledge, we propose four major focus areas: 1) policy and education; 2) clinical assessment; 3) basic and translational research; and 4) infrastructure and tools, and discuss future directions for advancement. This review is a follow-up of the discussions at the European Respiratory Society Research Seminar "Early origins of lung disease: towards an interdisciplinary approach" (Lisbon, Portugal, November 2019).

Abstract DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS‐CoV‐2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow‐up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation‐based machine learning models that distinguished samples from pre‐, during‐, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS‐CoV‐2 infection to the model‐defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS‐CoV‐2 epigenetic landscape we identify is antiprotective.

Introduction Allergic asthma commonly develops during early childhood. While it is difficult to precisely define the prevalence of children affected, it is now estimated that between 5% and 20% of [...], Allergic asthma generally starts during early life and is linked to substantial tissue remodeling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLSs), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MC) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-cadherin. Furthermore, spatial transcriptomics of pediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodeling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.

ABSTRACTWe present a detailed 1:50,000-scale glacial geomorphological map covering ∼450 km2 of the Wicklow Mountains, eastern Ireland. The region was glaciated at the Last Glacial Maximum, but little is known about the timing and pattern of deglaciation during the Last Glacial-Interglacial Transition or the extent of glacier regrowth during the Younger Dryas. The absence of detailed glacial geomorphological mapping has been a barrier to understanding these outstanding questions before now. Mapping of the area was compiled during field campaigns supported by the assessment of remotely-sensed imagery. Ice-marginal moraines are the most prevalent landform mapped and these have been classified into three groups based on differences in morphology. Other evidence for glaciation includes glacially-transported boulders, ice-moulded bedrock, meltwater channels, terraces, talus and summit blockfields. The map forms an essential basis for future work that will investigate glacial landsystems, deglaciation patterns and timing, and the style and extent of Younger Dryas glaciation.