Precision preclinical modeling to advance cancer treatment.

A new era of cancer management is underway in which treatments are being developed for the entire continuum of the disease process. The availability of genetically engineered and naturally occurring preclinical models serve as instructive platforms for evaluating therapeutic mechanisms. However, a major clinical challenge is that the entire malignancy process occurs across multiple scales including genetic mutations, malignant changes in cell behavior, dysregulated tumor microenvironments, and systemic adaptations in the host. A multi-disciplinary group of investigators coalesced at the National Cancer Institute Oncology Models Forum (NCI-OMF) with the overall goal to provide updates on the use of precision preclinical models of cancer. The benefits and limitations of preclinical models were discussed in order to identify strategies for maximizing opportunities in modeling that could inform future cancer prevention and treatment approaches. Our shared perspective is that the continuum of single cell, multi-cell, organoid, and in situ models are remarkable resources for the clinical challenges ahead. We provide a roadmap for parsing already available models and include preliminary recommendations for the application of next generation preclinical modeling in cancer intervention.

Podoplanin expressing macrophages and their involvement in tertiary lymphoid structures in mouse models of Sjögren's disease.

Tertiary lymphoid structures (TLSs) are formed in tissues targeted by chronic inflammation processes, such as infection and autoimmunity. In Sjögren's disease, the organization of immune cells into TLS is an important part of disease progression. Here, we investigated the dynamics of tissue resident macrophages in the induction and expansion of salivary gland TLS. We induced Sjögren's disease by cannulation of the submandibular glands of C57BL/6J mice with LucAdV5. In salivary gland tissues from these mice, we analyzed the different macrophage populations prior to cannulation on day 0 and on day 2, 5, 8, 16 and 23 post-infection using multicolored flow cytometry, mRNA gene analysis, and histological evaluation of tissue specific macrophages. The histological localization of macrophages in the LucAdV5 induced inflamed salivary glands was compared to salivary glands of NZBW/F1 lupus prone mice, a spontaneous mouse model of Sjögren's disease. The evaluation of the dynamics and changes in macrophage phenotype revealed that the podoplanin (PDPN) expressing CX3CR1+ macrophage population was increased in the salivary gland tissue during LucAdV5 induced inflammation. This PDPN+ CX3CR1+ macrophage population was, together with PDPN+CD206+ macrophages, observed to be localized in the parenchyma during the acute inflammation phase as well as surrounding the TLS structure in the later stages of inflammation. This suggests a dual role of tissue resident macrophages, contributing to both proinflammatory and anti-inflammatory processes, as well as their possible interactions with other immune cells within the inflamed tissue. These macrophages may be involved with lymphoid neogenesis, which is associated with disease severity and progression. In conclusion, our study substantiates the involvement of proinflammatory and regulatory macrophages in autoimmune pathology and underlines the possible multifaceted functions of macrophages in lymphoid cell organization.

Choice of alcohol over a natural reward: an experimental study in light and heavy social drinkers.

RATIONALE & OBJECTIVES: A core symptom of alcohol use disorder (AUD) is a progressively increased choice of alcohol over alternative rewards despite negative consequences. Here, we investigated choice between personalized alcohol vs. natural rewards in a laboratory setting, and compared this behavior between non-treatment-seeking heavy drinkers and light social drinkers. METHODS: 30 light social drinkers (15 men drinking < 15 drinks/week and 15 women drinking < 10 drinks/week) and 30 heavy, non-treatment-seeking drinkers (drinking more than these levels; 15 women). In the Concurrent Choice Alcohol Food (CCAF) task, participants chose between individually tailored images of alcohol and snack rewards and collected points towards the respective reward. To assess cost sensitivity, points associated to the images varied so that they favored alcohol or snack, or were equal, creating three relative point levels. RESULTS: Choice preference for alcohol was strongly correlated with Alcohol Use Disorder Identification Test (AUDIT) scores, supporting the external validity of the choice procedure. Compared to light drinkers, heavy drinkers showed increased choice preference for alcohol, as indicated by a between-group difference in points of subjective equality, a metric that quantifies the relative point level at which alcohol and snacks were equally likely to be chosen. In both groups, choice preference strongly depended on the relative point level of alcohol compared to snacks, suggesting that responding for alcohol in heavy drinkers was sensitive to costs. CONCLUSIONS: Our results replicate previous findings of a relationship between self-reported alcohol use and choice preference for alcohol. We also found that choice behavior was strongly dependent on relative cost of alcohol in both groups, although price sensitivity was lower in heavy compared to light drinkers. An increased choice preference for alcohol in heavy drinkers suggests that they attribute a higher relative reinforcing value to alcohol compared to natural rewards.

Uranium Repartitioning during Microbial Driven Reductive Transformation of U(VI)-Sorbed Schwertmannite and Jarosite.

This study exposes U(VI)-sorbed schwertmannite and jarosite to biotic reductive incubations under field-relevant conditions and examines the changes in aqueous and solid-phase speciation of U, Fe, and S as well as associated microbial communities over 180 days. The chemical, X-ray absorption spectroscopy, X-ray diffraction, and microscopic data demonstrated that the U(VI)-sorbed schwertmannite underwent a rapid reductive dissolution and solid-phase transformation to goethite, during which the surface-sorbed U(VI) was partly reduced and mostly repartitioned to monomeric U(VI)/U(IV) complexes by carboxyl and phosphoryl ligands on biomass or organic substances. Furthermore, the microbial data suggest that these processes were likely driven by the consecutive developments of fermentative and sulfate- and iron- reducing microbial communities. In contrast, the U(VI)-sorbed jarosite only stimulated the growth of some fermentative communities and underwent very limited reductive dissolution and thus, remaining in its initial state with no detectable mineralogical transformation and solid-phase U reduction/repartitioning. Accordingly, these two biotic incubations did not induce increased risk of U reliberation to the aqueous phase. These findings have important implications for understanding the interactions of schwertmannite/jarosite with microbial communities and colinked behavior and fate of U following the establishment of reducing conditions in various acidic and U-rich settings.

Genotypic variation in winter wheat for fusarium foot rot and its biocontrol using Clonostachys rosea.

Biological control to manage plant diseases is an environmentally friendly alternative to using chemical pesticides. However, little is known about the role of genetic variation in plants affecting the efficacy of biological control agents (BCAs). The aim of this study was to explore the genetic variation in winter wheat for disease susceptibility to fusarium foot rot caused by Fusarium graminearum and variation in biocontrol efficacy of the fungal BCA Clonostachys rosea to control the disease. In total, 190 winter wheat genotypes were evaluated under controlled conditions in two treatments, i.e. (i) F. graminearum (Fg) and (ii) F. graminearum infection on C. rosea treated seeds (FgCr). Alongside disease severity, plant growth-related traits such as shoot length and root length were also measured. Comparison of genotypes between the two treatments enabled the dissection of genotypic variation for disease resistance and C. rosea efficacy. The study revealed significant variation among plant genotypes for fusarium foot rot susceptibility and other growth traits in treatment Fg. Moreover, significant variation in C. rosea efficacy was also observed in genotype contrasts between the two treatments for all traits. Using a 20K marker array, a genome-wide association study was also performed. We identified a total of 18 significant marker-trait associations for disease resistance and C. rosea efficacy for all the traits. Moreover, the markers associated with disease resistance and C. rosea efficacy were not co-localized, highlighting the independent inheritance of these traits, which can facilitate simultaneous selection for cultivar improvement.

Betablockers and clinical outcome after surgical aortic valve replacement-a report from the SWEDEHEART registry.

OBJECTIVES: Previous reports suggest that betablockers appear non-beneficial after surgical aortic valve replacement (SAVR). This study aims to clarify the associations between betablockers and long-term outcome after SAVR. METHODS: All patients with isolated SAVR due to aortic stenosis in Sweden between 2006 and 2020, alive at six months after surgery, were included. Patients were identified in the SWEDEHEART registry and records were merged with data from three other mandatory national registries. Association between dispensed betablockers and MACE (all-cause mortality, myocardial infarction, stroke) was analyzed using Cox proportional hazards models, with time-updated data on medication and adjusted for age, sex, and comorbidities at baseline. RESULTS: In total, 11849 patients were included (median follow-up 5.4 years [range 0-13.5]). Betablockers were prescribed to 79.7% of patients at baseline, decreasing to 62.2% after 5 years. Continuing treatment was associated with higher risk of MACE (adjusted hazard ratio 1.14 [95% confidence interval 1.05-1.23]). The association was consistent over subgroups based on age, sex, and comorbidities except atrial fibrillation (HR 1.05 [95% CI 0.93-1.19]). A sensitivity analysis including time-updated data on comorbidites attenuated the difference between the groups (HR 1.04 [95% CI 0.95-1.14, p = 0.33]). CONCLUSIONS: Treatment with betablockers did not appear to be associated with inferior long-term outcome after SAVR, when adjusting for new concomitant diseases. Thus, it is likely that it is the underlying cardiac diseases that are associated with MACE rather than betablocker treatment.

Rational suicide? Interviews with Swedish psychiatrists.

Semi-structured interviews were performed with 12 psychiatrists regarding their perceptions of the Swedish Vision Zero for Suicide. Focusing on the topic of rational suicide, we re-analyzed these interviews using descriptive content analysis. The informants generally acknowledged the existence of rational suicide and its occurrence also among severely ill psychiatric patients, but expressed varying perceptions of the relevance of the concept in clinical practice. The difficulty of identifying rational suicide was considered to be a major problem. Another experience was a potential conflict between promoting a patient's rationality and preventing suicide. While the normative aspects of rational suicide have been addressed in the literature, our results highlight a need for further attention to the epistemological and practical aspects of rational suicide.

Genetic influences, lifestyle and psychosocial aspects in relation to metabolically healthy obesity and conversion to a metabolically unhealthy state.

AIMS: About 10%-30% of individuals with obesity are metabolically healthy, but the specific characteristics of the metabolically healthy obesity (MHO) phenotype remain unclear. We aimed to examine how physical activity, education, depressive symptoms and genetic predisposition to obesity differ between individuals with MHO and those with metabolically unhealthy obesity (MUO), and whether these factors predict stability in MHO or conversion to a metabolically unhealthy state. MATERIALS AND METHODS: We retrieved data on 9809 individuals with obesity from the Health and Retirement Study collected between 2006 and 2016. We compared how physical activity, education, depressive symptoms and a polygenic score for higher body mass index (BMI) (PGSBMI) differed cross-sectionally between MHO and MUO using logistic regression. We then examined if the same factors predict conversion to a metabolically unhealthy state over 4 years in individuals with MHO. RESULTS: Individuals with MHO had higher physical activity (odds ratio [OR] = 0.81), higher education (OR = 0.83) and lower depressive symptoms (OR = 1.14) compared to those with MUO but did not differ in the PGSBMI. The associations were slightly attenuated in mutually adjusted models. None of the factors were associated with conversion from MHO to a metabolically unhealthy state. However, a higher PGSBMI indicated 24% lower risk of conversion to a metabolically unhealthy state (p = 0.07). CONCLUSIONS: Physical activity, education and depressive symptoms differed between MHO and MUO, even when mutually adjusted for, but did not predict conversion from a metabolically healthy to unhealthy state. Although not statistically significant, the results indicated that those with genetically predicted high BMI are more likely to maintain MHO and not convert to a metabolically unhealthy state.

Sterol regulatory element-binding proteins mediate intrinsic fungicide tolerance and antagonism in the fungal biocontrol agent Clonostachys rosea IK726.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors governing various biological processes in fungi, including virulence and fungicide tolerance, by regulating ergosterol biosynthesis and homeostasis. While studied in model fungal species, their role in fungal species used for biocontrol remains elusive. This study delves into the biological and regulatory function of SREBPs in the fungal biocontrol agent (BCA) Clonostachys rosea IK726, with a specific focus on fungicide tolerance and antagonism. Clonostachys rosea genome contains two SREBP coding genes (sre1 and sre2) with distinct characteristics. Deletion of sre1 resulted in mutant strains with pleiotropic phenotypes, including reduced C. rosea growth on medium supplemented with prothioconazole and boscalid fungicides, hypoxia mimicking agent CoCl2 and cell wall stressor SDS, and altered antagonistic abilities against Botrytis cinerea and Rhizoctonia solani. However, Δsre2 strains showed no significant effect. Consistent with the gene deletion results, overexpression of sre1 in Saccharomyces cerevisiae enhanced tolerance to prothioconazole. The functional differentiation between SRE1 and SRE2 was elucidated by the yeast-two-hybridization assay, which showed an interaction between SREBP cleavage-activating protein (SCAP) and SRE1 but not between SRE2 and SCAP. Transcriptome analysis of the Δsre1 strain unveiled SRE1-mediated expression regulation of genes involved in lipid metabolism, respiration, and xenobiotic tolerance. Notably, genes coding for antimicrobial compounds chitinases and polyketide synthases were downregulated, aligning with the altered antagonism phenotype. This study uncovers the role of SREBPs in fungal BCAs, providing insights for C. rosea IK726 application into integrated pest management strategies.

Adipose stem cells are sexually dimorphic cells with dual roles as preadipocytes and resident fibroblasts.

Cell identities are defined by intrinsic transcriptional networks and spatio-temporal environmental factors. Here, we explored multiple factors that contribute to the identity of adipose stem cells, including anatomic location, microvascular neighborhood, and sex. Our data suggest that adipose stem cells serve a dual role as adipocyte precursors and fibroblast-like cells that shape the adipose tissue's extracellular matrix in an organotypic manner. We further find that adipose stem cells display sexual dimorphism regarding genes involved in estrogen signaling, homeobox transcription factor expression and the renin-angiotensin-aldosterone system. These differences could be attributed to sex hormone effects, developmental origin, or both. Finally, our data demonstrate that adipose stem cells are distinct from mural cells, and that the state of commitment to adipogenic differentiation is linked to their anatomic position in the microvascular niche. Our work supports the importance of sex and microvascular function in adipose tissue physiology.

Psychiatric disorders and comorbidity in women with Turner Syndrome: a retrospective national cohort study.

Turner syndrome (TS) is a genetic condition characterized by partial or complete monosomy X. A reduced life expectancy has been shown in TS, depending on an increased risk of aortic dissection, and ischemic heart disease. Studies covering the occurrence of psychiatric conditions are sparse within TS. Several case reports describe concomitant TS and neuropsychiatric abnormalities that may represent a pathogenetic link to genetics, as well as feature correlates of TS. The aim of this study was to determine the presence, and the frequency of psychiatric diagnosis in women with TS in a Swedish cohort followed during 25 years' time. Statistics from the entire female population in Sweden of corresponding age was used as reference. Data were retrieved from clinical examinations and validated from the National Board of Health and Welfare registries for women with TS (n = 487), aged 16 to 84 years, with respect to mental health disorders. The most common diagnoses in TS were mood and anxiety disorders. There was no increase in psychiatric diagnosis within the group with time, nor correlation to specific karyotype or somatic comorbidity as congenital heart disease and hypothyroidism, hormonal treatment, or childbirth. In addition, the frequency of psychiatric diagnosis in TS was lower than in the population-based data. Further investigations are needed in the view of the fact that women with Turner syndrome should not be burdened with more severe diagnoses.

Transcriptomic and functional analyses on a Botrytis cinerea multidrug-resistant (MDR) strain provides new insights into the potential molecular mechanisms of MDR and fitness.

Botrytis cinerea is a notorious pathogen causing pre- and post-harvest spoilage in many economically important crops. Excessive application of site-specific fungicides to control the pathogen has led to the selection of strains possessing target site alterations associated with resistance to these fungicides and/or strains overexpressing efflux transporters associated with multidrug resistance (MDR). MDR in B. cinerea has been correlated with the overexpression of atrB and mfsM2, encoding an ATP-binding cassette (ABC) and a major facilitator superfamily (MFS) transporter, respectively. However, it remains unknown whether other transporters may also contribute to the MDR phenotype. In the current study, the transcriptome of a B. cinerea multidrug-resistant (MDR) field strain was analysed upon exposure to the fungicide fludioxonil, and compared to the B05.10 reference strain. The transcriptome of this field strain displayed significant differences as compared to B05.10, including genes involved in sugar membrane transport, toxin production and virulence. Among the induced genes in the field strain, even before exposure to fludioxonil, were several putatively encoding ABC and MFS transmembrane transporters. Overexpression of a highly induced MFS transporter gene in the B05.10 strain led to an increased tolerance to the fungicides fluopyram and boscalid, indicating an involvement in efflux transport of these compounds. Overall, the data from this study give insights towards better understanding the molecular mechanisms involved in MDR and fitness cost, contributing to the development of more efficient control strategies against this pathogen.

A new patient-reported outcome measure for the evaluation of ankle instability: description of the development process and validation protocol.

BACKGROUND: Acute ankle sprains represent one of the most common traumatic injuries to the musculoskeletal system. Many individuals with these injuries experience unresolved symptoms such as instability and recurrent sprains, leading to chronic ankle instability (CAI), which affects their ability to maintain an active lifestyle. While rehabilitation programs focusing on sensorimotor, neuromuscular, strength and balance training are primary treatments, some patients require surgery when rehabilitation fails. A critical analysis of the patient-reported outcome tools (PROs) used to assess CAI surgical outcomes raises some concerns about their measurement properties in CAI patients, which may ultimately affect the quality of evidence supporting current surgical practice. The aim of this research is to develop and validate a new PRO for the assessment of ankle instability and CAI treatment outcomes, following recent methodological guidelines, with the implicit aim of contributing to the generation of scientifically meaningful evidence for clinical practice in patients with ankle instability. METHODS: Following the COnsensus-based Standards for the selection of Health Measurement Instruments (COSMIN), an Ankle Instability Treatment Index (AITI) will be developed and validated. The process begins with qualitative research based on face‒to‒face interviews with CAI individuals to explore the subjective experience of living with ankle instability. The data from the interviews will be coded following an inductive approach and used to develop the AITI content. The preliminary version of the scale will be refined through an additional round of face‒to‒face interviews with a new set of CAI subjects to define the AITI content coverage, relevance and clarity. Once content validity has been examined, the AITI will be subjected to quantitative analysis of different measurement properties: construct validity, reliability and responsiveness. DISCUSSION: The development of AITI aims to address the limitations of existing instruments for evaluating surgical outcomes in patients with CAI. By incorporating patient input and adhering to contemporary standards for validity and reliability, this tool seeks to provide a reliable and meaningful assessment of treatment effects. TRIAL REGISTRATION: Not applicable.

New histological risk grading system for prediction of lymph node metastasis in patients with penile cancer.

Inguinal lymph node surgery is a standard treatment for penile cancer patients with intermediate or high risk for lymph node metastasis (LNM) according to European Association of Urology (EAU) risk grading. We are proposing a more objective histological prognostic grading system for inguinal LNM in these patients. We assessed worst pattern of invasion, lymphocytic host response, lymphovascular invasion, and perineural invasion in a population-based cohort of 306 penile cancer patients. Patients were classified into low, intermediate, and high risk for inguinal LNM. There was a significant association both between risk groups and pT stage (p < 0.001) and between risk groups and LNM. Univariate logistic regression showed 25.43 times higher odds of LNM for patients in the intermediate risk group compared with the low risk group (odds ratio (OR) 25.43; 95% confidence interval (CI): 5.94-108.97) and a 177.13 times higher odds in the high risk group compared to the low risk group (OR 177.13; 95% CI: 40.09-782.51). When comparing our histological risk grading with the EAU grading, we found a higher sensitivity, of 51.28% (95% CI: 45.68-56.88) versus 37.09% (95% CI: 31.68-42.50), as well as a higher area under the curve (0.86; 95% CI: 0.81-0.89; versus 0.65; 95% CI: 0.58-0.71) with our grading system. While our grading classified 111 patients as low risk, only 31 were considered low risk for LNM according to the EAU risk classification. The new histological risk grading system shows a higher sensitivity and includes a higher number of patients in the low risk group in whom lymph node surgery could be avoided, reducing morbidity and costs.

Diabetic Peripheral Neuropathy: Emerging Treatments of Neuropathic Pain and Novel Diagnostic Methods.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain. METHODS: In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects. RESULTS: Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates. CONCLUSION: Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.

Older adults' experiences of being screened for fall risk in a clinical setting: a focus group study.

PURPOSE: There is a need for further research on older adults' experiences of fall risk screening to improve health communication strategies. The purpose of this study was to describe and explore older adults' experiences of being screened for risk of an injurious fall, using the first-time injurious falls (FIF) screening tool. METHODS: A qualitative study with five focus group interviews was carried out including 17 older adults (11 women and six men, with a mean age of 77.4 years) who were recruited from two primary healthcare rehabilitation clinics in Sweden. Data were analyzed using reflexive thematic analysis. RESULTS: The analysis generated one overarching theme, "Screening for fall risk promotes engagement by raising older adults' awareness of their own abilities", and four categories; "Screening may motivate to take action but can also create a false sense of security", "Self-sufficiency is affected by the screening result and level of control over the environment", "Easy-to-perform and helps to facilitate a discussion with the healthcare professional" and "Ideas of how FIF tool could be used in healthcare". CONCLUSION: Older adults considered screening for fall risk to be meaningful insofar as it raises awareness of their own abilities and motivates them to prevent falls. On the other hand, a low fall risk could create a false sense of security, and lack of control over environmental factors related to fall risk could negatively impact their sense of self-sufficiency. They emphasized the need to receive support from healthcare providers and to be involved in care decisions if the screening indicates a high fall risk.

Prevalence and Trends of Not Receiving a Dose of DPT-Containing Vaccine Among Children 12-35 Months: An Analysis of 81 Low- And Middle-Income Countries.

Not receiving a DPT-containing vaccine in early childhood indicates an absence of routine immunization, which puts children at an elevated risk of mortality, morbidity, and worse human development over the life course. We estimated the percentage of children 12-35 months who did not receive a dose of DPT-containing vaccine (termed zero-dose children) using household surveys from 81 low- and middle-income countries conducted between 2014 and 2023. For 68 countries with more than one survey (with the earlier survey conducted 2000-2013), we estimated the average annual percentage point change in prevalence of zero-dose children between the earliest and latest surveys. We also explored the association of zero-dose prevalence with postneonatal and child mortality, health expenditure, and Gavi-eligibility. Overall, 16% of children in our pooled sample had not received a dose of DPT-containing vaccine. There was a 0.8% point decline in zero-dose prevalence per year on average across the period studied. A single percentage point average annual decline in zero-dose prevalence was associated with an average annual decrease of 1.4 deaths in the postneonatal and childhood period per 1000 live births. Gavi-eligible countries had a much faster decline in zero-dose prevalence than other countries. Large gains have been made in reducing the percentage of children who did not receive a DPT-containing vaccine. Efforts to reduce the number of zero-dose children should focus on countries with high prevalence to achieve the Immunization Agenda 2030. Healthcare spending could be prioritized so that the prevalence of zero-dose children is reduced.

SARS-CoV-2 infection induces hyaluronan production in vitro and hyaluronan levels in COVID-19 patients relate to morbidity and long-term lung impairment: a prospective cohort study.

We previously demonstrated that the lungs of deceased COVID-19 patients were filled with a clear hydrogel consisting of hyaluronan (HA). In this translational study, we investigated the role of HA at all stages of COVID-19 disease to map the consequences of elevated HA on morbidity and identify the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced HA production. A reduced alveolar surface area was observed in the lungs of deceased COVID-19 patients compared to healthy controls, as visualized by a 3D rendering of lung morphology using light-sheet fluorescence microscopy. We confirmed the presence of HA in lung biopsies and found large quantities of proinflammatory fragmented HA. The association of systemic HA in blood plasma and disease severity was assessed in patients with mild (WHO Clinical Progression Scale, WHO-CPS, 1-5) and severe COVID-19 (WHO-CPS, 6-9) during the acute and convalescent phases and related to lung function. We found that systemic levels of HA were high during acute COVID-19 disease, remained elevated during convalescence, and were associated with a reduced diffusion capacity. In vitro 3D-lung models, differentiated from primary human bronchial epithelial cells, were used to study the effects of SARS-CoV-2 infection on HA metabolism, and transcriptomic analyses revealed a dysregulation of HA synthases and hyaluronidases, both contributing to increased HA in apical secretions. Furthermore, corticosteroid treatment reduced the inflammation and downregulated HA synthases. Our findings demonstrate that HA plays a role in COVID-19 morbidity and that sustained elevated HA concentrations may contribute to long-term respiratory impairment.IMPORTANCEThis study provides insights into the role of hyaluronan (HA) in the severity and long-term impact of COVID-19 on lung function. Through extensive morphological examination of lung tissues and a multicenter study, we identified that HA levels are significantly elevated in COVID-19 patients, correlating with a reduced lung diffusion capacity during convalescence. Using a 3D-lung model, we further uncovered how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection causes a dysregulated HA metabolism, leading to increased HA production. Our findings provide valuable insights into the pathogenesis of SARS-CoV-2 and suggest that targeting HA metabolism could offer new therapeutic avenues for managing COVID-19, particularly to prevent long-term lung impairment. Additionally, HA holds potential as a biomarker for predicting disease severity, which could guide personalized treatment strategies.

Carbon emission from the Lower Ob River floodplain during spring flood.

Carbon emission from Arctic rivers constitutes a positive feedback between the climate warming and C cycle. However, in case of rivers with extensive floodplains, the impacts of temporary water bodies and secondary channels on CO2 exchange with atmosphere, compared to the main stem and tributaries, remain strongly understudied. In order to quantify the relative role of various water bodies of the Arctic river basin in the C cycle, the hydrochemical variables and greenhouse gases GHG concentrations and fluxes were measured within the floodplain of the largest Arctic River, Ob, in its low reaches located in the permafrost zone. These included the main stem, secondary channels, tributaries and floodplain lakes sampled over a 900 km north-south transect (25,736 km2 of the main stem and adjacent floodplain area; 7893 km2 water surface) during peak of spring flood (May 2023). In addition to main stem and tributaries, providing less than a half of overall C flux, floodplain lakes and secondary channels acted as important factor of C emission from the floodplain water surfaces. Multi-parametric statistical treatment of the data suggested two main processes of C emission from the Ob River floodplain waters: terrestrial organic matter-rich flooded wetlands (fens) provided elevated pCO2, whereas the sites of possible groundwater discharge in the secondary channels decreased the CO2 fluxes due to more alkaline environments, rich in labile metals and anionic elements. Based on available high-resolution Landsat-8 images, which matched the period of field work, it was found that the total water coverage of the floodplain during spring 2023 was 30 % of overall territory, compared to 18 % during the baseflow. Based on chamber-measured CO2 fluxes (1.56 ± 0.47 g C-CO2 m-2 d-1), overall CO2 emissions during 2 months of the spring flood from the entire Lower Ob River floodplain water surfaces including the main stem amounted to 0.73 ± 0.25 Tg C. Diffuse CH4 flux represented <1 % of total C flux. The main stem of the Ob River accounted for 34 % and 18 % of CO2 and CH4 emissions, respectively, whereas the floodplain lakes provided 59 % and 50 % of CO2 and CH4 emission, respectively. Considering that the low reaches of the Ob River represent >70 % of total river basin floodplain, and that during some years, the entire floodplain can be covered by water, emissions from the river - if assessed solely from summer (July-August) measurements - can be at least 3 times underestimated. It is therefore important to account for extended water surface during high water levels on Arctic rivers when assessing global riverine C emissions.

A detailed analysis of body composition in relation to cardiopulmonary exercise test indices.

A cardiopulmonary exercise test (CPET) is a test assessing an individual's physiological response during exercise. Results may be affected by body composition, which is best evaluated through imaging techniques like magnetic resonance imaging (MRI). The aim of this study was to assess relationships between body composition and indices obtained from CPET. A total of 234 participants (112 female), all aged 50 years, underwent CPETs and whole-body MRI scans (> 1 million voxels). Voxel-wise statistical analysis of tissue volume and fat content was carried out with a method called Imiomics and related to the CPET indices peak oxygen consumption (V̇O2peak), V̇O2peak scaled by body weight (V̇O2kg) and by total lean mass (V̇O2lean), ventilatory efficiency (V̇E/V̇CO2-slope), work efficiency (ΔV̇O2/ΔWR) and peak exercise respiratory exchange ratio (RERpeak). V̇O2peak showed the highest positive correlation with volume of skeletal muscle. V̇O2kg negatively correlated with tissue volume in subcutaneous fat, particularly gluteal fat. RERpeak negatively correlated with tissue volume in skeletal muscle, subcutaneous fat, visceral fat and liver. Some associations differed between sexes: in females ΔV̇O2/ΔWR correlated positively with tissue volume of subcutaneous fat and V̇E/V̇CO2-slope with tissue volume of visceral fat, and, in males, V̇O2peak correlated positively to lung volume. In conclusion, voxel-based Imiomics provided detailed insights into how CPET indices were related to the tissue volume and fat content of different body structures.