Search

Increased ventilator use during the COVID-19 pandemic resurrected persistent questions regarding mechanical ventilation including the difference between physiological and artificial breathing induced by ventilators (i.e., positive- versus negative-pressure ventilation, PPV vs NPV). To address this controversy, we compare murine specimens subjected to PPV and NPV in ex vivo quasi-static loading and quantify pulmonary mechanics via measures of quasi-static and dynamic compliances, transpulmonary pressure, and energetics when varying inflation frequency and volume. Each investigated mechanical parameter yields instance(s) of significant variability between ventilation modes. Most notably, inflation compliance, percent relaxation, and peak pressure are found to be consistently dependent on the ventilation mode. Maximum inflation volume and frequency note varied dependencies contingent on the ventilation mode. Contradictory to limited previous clinical investigations of oxygenation and end-inspiratory measures, the mechanics-focused comprehensive findings presented here indicate lung properties are dependent on loading mode, and importantly, these dependencies differ between smaller versus larger mammalian species despite identical custom-designed PPV/NPV ventilator usage. Results indicate that past contradictory findings regarding ventilation mode comparisons in the field may be linked to the chosen animal model. Understanding the differing fundamental mechanics between PPV and NPV may provide insights for improving ventilation strategies and design to prevent associated lung injuries.

Objective: Well-designed patient education materials (PEMs) increase health literacy, which has been linked to better surgical patient outcomes. The quality of lung cancer surgery PEMs is unknown, however. Here we assessed printed lung cancer surgery PEMs for readability, understandability, actionability, and accessibility. Methods: Various lung cancer programs throughout the United States were contacted for their lung cancer surgery PEMs. The readability of the received materials was calculated using 6 readability tests. Four thoracic surgeon–advanced practice practitioner dyads scored the PEMs for understandability, actionability, and accessibility using the Patient Education Material Assessment Tool and the Accessibility Assessment Tool, with the recommended minimum threshold of 70%. One-sample t tests were performed to compare each parameter against its recommended threshold. Results: Out of 34 institutions contacted, 18 (52.9%) provided PEMs. The average reading level of the PEMs ranged from 7th grade to 11th grade, significantly exceeding the recommended 6th grade health literacy threshold (P

Abstract Background Depression is a common and serious problem in older adults, but few have access to psychological treatments. Internet-delivered Cognitive Behavioral Therapy (ICBT) has the potential to improve access and has been found to be effective in adults with depression. The aim of this study was to examine the effects of tailored ICBT for depression in older adults aged 65 years or older. We also investigated if cognitive flexibility could predict outcome. Methods Following online recruitment from the community, included participants were randomly allocated to either ten weeks of clinician guided ICBT (n = 50) or to an active control group in the form of non-directive support (n = 51). Primary depression outcome was the Geriatric Depression Scale (GDS-15). Several secondary outcomes were used, such as the Beck Depression Inventory (BDI-II) and the Patient Health Questionnaire (PHQ-9). Results Both treatment and active control groups significantly reduced their levels of depression, and the treatment group showed significantly greater improvement on the GDS-15 and BDI-II, but not on the PHQ-9. Between-group effect sizes as Cohen’s d were 0.78 (CI95% 0.36–1.20) on the GDS-15 and 0.53 (CI95% 0.11–0.94) on the BDI-II. Conclusions Tailored ICBT is superior to an active control for older adults with depression. Between-group effects were smaller than in previous RCTs, most likely because of the use of an active control condition. Cognitive flexibility did not predict outcome. We conclude that ICBT can be used for older adults with depression, and thus increase access to psychotherapy for this group. Trial registration This trial was retrospectively registered in clinicaltrials.gov (no. NCT05269524) the 8th of March 2022.

Abstract Background Disparities in breast cancer mortality persist despite improvements in screening and therapeutic options. Understanding the impact of social determinants of health on disparate breast cancer outcomes is challenging due to heterogeneity of prior assessments. We examined the association between social vulnerability and breast cancer stage at diagnosis and mortality using a standardized measure of population risk for external stressors on health. Methods Using institutional cancer registry data, female patients aged 18 or older diagnosed with breast cancer between 2012 and 2019 were assigned a 2018 Social Vulnerability Index (SVI) rank based upon home address census tract. We used multinomial logistic regression and Cox proportional hazards model to examine the relationships between SVI and breast cancer stage at diagnosis and all-cause mortality. Covariates included age and, when assessing mortality, cancer stage, comorbidities, body mass index, insurance type, and treatment regimen. Results A total of 3,499 women with a median age of 59 (IQR 48–69) were included. 60% were White and 31% were Black. Median SVI was 0.36 (IQR 0.14–0.68) and median follow-up was 58 months (IQR 37.3–83.9). On adjusted analyses, each decile increase in SVI resulted in an 11% (OR 1.11, 95% CI 1.06–1.16, p

Abstract Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi‐step, challenging, and time‐consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open‐source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter‐individual variability (IIV) model, the inter‐occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development.

Summary: Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency. We collected clinical and molecular data from 26 individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including 20 previously unreported cases. By comparing their DNA methylation (DNAm) classifiers with those of healthy controls and other neurodevelopmental disorders characterized by established episignatures, we aimed to create a diagnostic biomarker (episignature) and gain more knowledge of the molecular pathophysiology. We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene. Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings. In addition, we performed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases. We discovered a highly accurate DNAm episignature serving as a robust diagnostic biomarker for NEDAUS. Furthermore, we broadened the phenotypic spectrum by identifying 20 new individuals and confirming five previously reported cases of NEDAUS.

PurposeDominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.MethodsWe used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.ResultsWe found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.ConclusionOur study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

A 1D imaging soft X-ray spectrometer installed on the small quantum systems (SQS) scientific instrument of the European XFEL is described. It uses movable cylindrical constant-line-spacing gratings in the Rowland configuration for energy dispersion in the vertical plane, and Wolter optics for simultaneous 1D imaging of the source in the horizontal plane. The soft X-ray fluorescence spectro-imaging capability will be exploited in pump–probe measurements and in investigations of propagation effects and other nonlinear phenomena.

ABSTRACT Introduction There are few accurate prognostic indications of the illness's development and severity for COVID‐19, despite certain biomarkers having been investigated. The unexpected nature of COVID‐19's course, which can quickly progress from asymptomatic to life‐threatening symptoms, lies at the heart of the disease's intricacy. Predicting SARS‐CoV‐2 pathogenicity through laboratory biomarkers and as such, identifying the patients’ illness severity at the time of their initial admission would be crucial in improving patient care. In this study, we sought to evaluate the potential of hematological, biochemical, and inflammatory biomarkers in predicting the course of COVID‐19 at a tertiary hospital in western Kenya. Methods This cross‐sectional study involved 48 COVID‐19 patients (16 asymptomatic; 16 moderate symptomatic; and 16 severe symptomatic) and 48 age‐sex‐matched COVID‐19‐negative clients attending the Moi Teaching and Referral Hospital, Kenya. Demographic information, self‐reported chronic illnesses, symptoms, and laboratory results were collected at recruitment. Results Significantly, the severity of COVID‐19 was associated with; hemoglobin (p

Agriculture dust contains many organic immunogenic compounds, and organic dust exposure is strongly associated with the development of immune-mediated chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD). Chronic organic dust exposure from agriculture sources induces chronic lung inflammatory diseases and organic dust exposure has recently been linked to an increased risk of developing dementia. The cytokine interleukin-22 (IL-22) has been established as an important mediator in the resolution and repair of lung tissues. The omega-3 fatty acid metabolite aspirin-triggered Resolvin D1 (AT-RvD1) has shown efficacy in modulating the immune response in both pulmonary and neurological inflammation but has not been explored as a therapeutic in organic dust exposure-induced neuroinflammation. Investigating the link between IL-22 and AT-RvD1 may help in developing effective therapies for these immune-mediated diseases. We aimed to investigate the link between organic dust exposure and neuroinflammation, the role of IL-22 in the pulmonary and neurological immune response to organic dust exposure, and the immune-modulating therapeutic applications of AT-RvD1 in an IL-22 knock-out mouse model of organic dust exposure. C57BL/6J (WT) and IL-22 knock-out (KO) mice were repetitively exposed to aqueous agriculture organic dust extract (DE) 5 days per week for 3 weeks (15 total instillations) and treated with AT-RvD1 either once per week (3 total injections) or 5 times per week (15 total injections) for 3 weeks and allowed to recover for 3 days. We observed a significant pulmonary and neurological immune response to DE characterized by the development of inducible bronchus associated lymphoid tissue in the lung and gliosis in the frontal areas of the brain. We also observed that IL-22 knock-out increased pulmonary and neurological inflammation severity. Animals exposed to DE and treated with AT-RvD1 displayed reduced lung pathology severity and gliosis. Our data demonstrate that DE exposure contributes to neurological inflammation and that IL-22 is crucial to effective tissue repair processes. Our data further suggest that AT-RvD1 may have potential as a novel therapeutic for organic dust exposure-induced, immune-mediated pulmonary and neurological inflammation, improving outcomes of those with these diseases.

Introduction Chronic primary pelvic pain syndrome (CPPPS) is a condition characterised by pain in the pelvic area together with lower urinary tract symptoms. Pathophysiology remains largely unclear. Common treatment modalities show unsatisfactory results. This randomised controlled trial aims to establish the long-term effect of pelvic floor re-education using biofeedback and home training for men with CPPPS evaluated with the National Institute of Health–Chronic Prostatitis Symptom Index (NIH-CPSI) and to explore if outcomes can be correlated to changes in objective urodynamic measures.Methods and analysis After inclusion all study participants will go through baseline testing consisting of urodynamic evaluation, assessment of the pelvic floor muscles and the NIH-CPSI questionnaire, thereafter, randomised to intervention or control group. Intervention consists of short daily session of pelvic floor muscle training, during 6 months. Parallelly with starting up, the intervention group will attend four bio-feedback sessions, to guide and facilitate the training. The training will initially aim on how to correctly activate and relax the pelvic floor muscles with functional enhancement further on. The control group will be offered to enter the intervention group after the 6-month assessment. The outcome will be assessed by repeating the baseline tests at 3, 6 and 12 months.To compare the primary outcome, the NIH-CPSI questionnaire between and within the two groups will be analysed. Secondary outcomes are the differences in sub-score reduction according to the domains in the NIH-CPSI questionnaire, the manual assessment of the pelvic floor muscles and numerical results from the urodynamic testing. The correlation between subjective and objective outcomes will be analysed.Ethics and dissemination The study obtained ethical approval from the Swedish Ethical Review Authority (2023-00286-01). The study result will be published in a peer-reviewed medical journal and presented at an international conference.Trial registration number This trial is registered at Clinicaltrials.gov (NCT06115083).

Ultraviolet rays are known to have positive effect on psoriasis, but the cold climate and latitude in Northern Europe reduce access to the sun. Climatotherapy is a treatment modality where the patient is relocated to a warmer region with a high ultraviolet (UV) index. Young patients with psoriasis can be particularly burdened by the disease, and studies have shown an association between psoriasis and mood disorders. Patients who have undergone climatotherapy often report beneficial psychological effects after treatment, but this has not yet been studied. To explore the psychosocial impact of climatotherapy, an observational study was designed. Thirty-four participants (median age of 24 years) underwent 3 weeks of treatment in Gran Canaria (Spain) and responded to questionnaires assessing the psychosocial aspects of the disease. Climatotherapy was associated with significantly reduced scores of HADS, PSS-10, PSQ, EQ-VAS, DLQI, and itch intensity at the end of and at 3 months after the end of treatment compared to before treatment onset. The results suggest that climatotherapy not only exerts effects on psoriasis skin disease but also improves symptoms of anxiety, depression, perceived stigmatization, stress, quality of life, self-assessed overall health perception, and itch intensity. The results can be of use in the decision-making process when choosing a suitable treatment for young patients with psoriasis.

Tissue remodeling in pulmonary disease irreversibly alters lung functionality and impacts quality of life. Mechanical ventilation is amongst the few pulmonary interventions to aid respiration, but can be harmful or fatal, inducing excessive regional (i.e., local) lung strains. Previous studies have advanced understanding of diseased global-level lung response under ventilation, but do not adequately capture the critical local-level response. Here, we pair a custom-designed pressure-volume ventilator with new applications of digital image correlation, to directly assess regional strains in the fibrosis-induced ex-vivo mouse lung, analyzed via regions of interest. We discuss differences between diseased and healthy lung mechanics, such as distensibility, heterogeneity, anisotropy, alveolar recruitment, and rate dependencies. Notably, we compare local and global compliance between diseased and healthy states by assessing the evolution of pressure-strain and pressure-volume curves resulting from various ventilation volumes and rates. We find fibrotic lungs are less-distensible, with altered recruitment behaviors and regional strains, and exhibit disparate behaviors between local and global compliance. Moreover, these diseased characteristics show volume-dependence and rate trends. Ultimately, we demonstrate how fibrotic lungs may be particularly susceptible to damage when contrasted to the strain patterns of healthy counterparts, helping to advance understanding of how ventilator induced lung injury develops.

The role of pulmonary free fatty acid receptor 4 (FFAR4) is not fully elucidated and we aimed to clarify the impact of FFAR4 on the pulmonary immune response and return to homeostasis. We employed a known high-risk human pulmonary immunogenic exposure to extracts of dust from swine confinement facilities (DE). WT and Ffar4-null mice were repetitively exposed to DE via intranasal instillation and supplemented with docosahexaenoic acid (DHA) by oral gavage. We sought to understand if previous findings of DHA-mediated attenuation of the DE-induced inflammatory response are FFAR4-dependent. We identified that DHA mediates anti-inflammatory effects independent of FFAR4 expression, and that DE-exposed mice lacking FFAR4 had reduced immune cells in the airways, epithelial dysplasia, and impaired pulmonary barrier integrity. Analysis of transcripts using an immunology gene expression panel revealed a role for FFAR4 in lungs related to innate immune initiation of inflammation, cytoprotection, and immune cell migration. Ultimately, the presence of FFAR4 in the lung may regulate cell survival and repair following immune injury, suggestive of potential therapeutic directions for pulmonary disease.

Worldwide, approximately one fifth of all cases of diarrhea are associated with norovirus, mainly in children, with a defined seasonality in temperate climates, but seasonal dynamics are less known in tropical climates. The objective was to investigate the impact of external clinical, epidemiological, and climatic factors on norovirus detection rates in samples from children under 5 years of age from Roraima, the Amazon region of Brazil. A total of 941 samples were included. According to climatic factors, we observed correlations between external climatic factors and weekly positivity rates, where temperature (P = 0.002), relative humidity (P = 0.0005), absolute humidity (P

Hur vanligt är det att studenter bedriver projekt som inbegriper etiskt känsligt innehåll? I denna artikel redogörs för en undersökning rörande ett högskolepedagogiskt utvecklingsarbete som avser formaliserad etikprövning av studentuppsatser. Undersökningen inbegriper uppsatser som examinerats och godkänts vid fakulteten för hälsa och samhälle vid Malmö universitet under åren 2014–2017. Med etiskt känsligt innehåll avses här känsliga personuppgifter samt intervenerande metoder, som vid forskning kräver etikprövning enligt lag (2003:460) om etikprövning av forskning som avser människor. Av totalt 1215 granskade uppsatser hade 277 (22,8 %) etiskt känsligt innehåll; vanligast var känsliga personuppgifter avseende hälsa. 165 (13.6 %) uppsatser innehöll sådana uppgifter. Etiskt känsligt innehåll var mer vanligt förekommande i uppsatser på avancerad nivå (32,9 %) än på grundnivå (20,4 %). Var femte student på grundnivå genomförde alltså studier som skulle ha krävt Etikprövningsmyndighetens godkännande om de hade varit forskare. Enligt fakultetens riktlinjer ska samtliga studentarbeten med ett innehåll som skulle ha krävt förhandsprövning vid forskning förhandsprövas av fakultetens etikråd för studentarbeten. Men endast 191 av de 277 uppsatser (68,9%) som borde ha genomgått sådan handläggning passerade etikrådet. Implementeringen av formaliserad etikprövning av uppsatsprojekt tycks fungera bäst då studentens handledare är forskarutbildad och kan antas ha egen erfarenhet av etikprövning. Vår undersökning visade också att etikprövningen implementerats i olika grad vid olika institutioner. I artikeln diskuteras möjliga förklaringar till denna skillnad. English abstract Ethical Review of Student Projects: The Responsibility of Higher Education Institutions How common is it for students to undertake projects involving ethically sensitive content? This article presents a study on higher education pedagogical development project concerning the formalized ethical review of student essays. The survey included essays that were examined and approved at the Faculty of Health and Society, Malmö university during 2014–2017. Ethically sensitive content refers here to sensitive personal data and intervention methods that, in research, require ethical review according to the Act (2003:460) on ethical review of research involving humans. Out of a total of 1215 examined thesis, 277 (22.8%) contained ethically sensitive content; the most common being personal health-related data. 165 (13.6%) essays contained such information. Advanced level theses had a higher prevalence of ethically sensitive content (32.9%) compared to undergraduate theses (20.4%). This indicates that a significant proportion of undergraduate students undertook projects involving content that would require ethical review if they were researchers. The faculty’s guidelines stipulate that all student works containing content requiring prior ethical review in research, should be reviewed by the faculty’s ethics council. However, only 68.9% of the essays that necessitated such review passed the ethics council, indicating a gap in compliance with ethical review processes. The study suggests that the effectiveness of formalized ethical review of thesis projects is enhanced when the student’s supervisor holds a doctoral degree, likely due to their familiarity and experience with ethical review procedures. Furthermore, the research highlights variations in the implementation of ethical review across different departments within the faculty. The article delves into possible reasons for these discrepancies.

Hantaviruses cause the acute zoonotic diseases hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Infected patients show strong systemic inflammation and immune cell activation. NK cells are highly activated in HFRS, suggesting that also other innate lymphoid cells (ILCs) might be responding to infection. Here, we characterized peripheral ILC responses, and measured plasma levels of soluble factors and plasma viral load, in 17 Puumala virus (PUUV)-infected HFRS patients. This revealed an increased frequency of ILC2 in patients, in particular the ILC2 lineage-committed c-Kitlo ILC2 subset. Patients' ILCs showed an activated profile with increased proliferation and displayed altered expression of several homing markers. How ILCs are activated during viral infection is largely unknown. When analyzing PUUV-mediated activation of ILCs in vitro we observed that this was dependent on type I interferons, suggesting a role for type I interferons-produced in response to virus infection-in the activation of ILCs. Further, stimulation of naïve ILC2s with IFN-β affected ILC2 cytokine responses in vitro, causing decreased IL-5 and IL-13, and increased IL-10, CXCL10, and GM-CSF secretion. These results show that ILCs are activated in HFRS patients and suggest that the classical antiviral type I IFNs are involved in shaping ILC functions.

Although it is widely recognised by language teachers that the use of musical activities supports language development in both children and adults, studies show that teachers do not use them as much as they would like. This gap can be disadvantageous to both learners and teachers. The purpose of this study was to collect examples of music activities that actually take place and are regarded as beneficial for language development in Spanish in a Swedish school context, and what conditions are central to them being used. The study is based on a survey and follow-up interviews with Spanish teachers, and the results show that a wide variety of activities are used, both with a focus on communicative and cultural competences, and on providing stimulating settings for learning. This high level of use suggests a smaller gap between teachers' beliefs and practices compared to previous studies, possibly indicating that music has a more prominent place in the Spanish classroom than in other foreign language classrooms. The choice of music for the learning activity emerged as a particularly important factor for the activity to work as intended. Sammanfattning (Svenska) Olika typer av musikaktiviteter kan gynna språkutvecklingen för såväl barn som vuxna, men flera studier visar att lärare inte använder dem i den utsträckning de skulle vilja. Detta glapp kan vara till nackdel för både inlärare och lärare. Syftet med denna studie var att samla exempel på musikaktiviteter som faktiskt blir av och bedöms fungera positivt för språkutveckling i spanska i svensk skolkontext, och vilka förutsättningar som är centrala för att detta ska ske. Studien baserar sig på enkätsvar och uppföljande intervjuer med spanskalärare, och resultaten visar att en stor variation av aktiviteter används både med fokus på kommunikativa och kulturella kompetenser, och för att främja förutsättningarna för lärande. Denna höga användning tyder på ett mindre glapp mellan övertygelse och praktik inom just spanskämnet, vilket kan tyda på att musik har en mer given plats i spanskaklassrummet än i andra språkämnen. Musikval framstår som en särskilt viktig faktor för att aktiviteten ska fungera med avsedd effekt.

Abstract Turner syndrome is a genetic condition caused by a complete or partial loss of one of the X chromosomes. Previous studies indicate that Turner syndrome is associated with challenges in social skills, but the underlying mechanisms remain largely unexplored. A possible mechanism is a reduced social influence on learning. The current study examined the impact of social and non-social feedback on learning in women with Turner syndrome (n = 35) and a sex- and age-matched control group (n = 37). Participants were instructed to earn points by repeatedly choosing between two stimuli with unequal probabilities of resulting in a reward. Mastering the task therefore required participants to learn through feedback which of the two stimuli was more likely to be rewarded. Data were analyzed using computational modeling and analyses of choice behavior. Social feedback led to a more explorative choice behavior in the control group, resulting in reduced learning compared to non-social feedback. No effects of social feedback on learning were found in Turner syndrome. The current study thus indicates that women with Turner syndrome may be less sensitive to social influences on reinforcement learning, than the general population.

In agriculture industries, workers are at increased risk for developing pulmonary diseases due to inhalation of agricultural dusts, particularly when working in enclosed confinement facilities. Agricultural dusts inhalation leads to unresolved airway inflammation that precedes the development and progression of lung disease. We have previously shown beneficial effects of the omega-3 polyunsaturated fatty acid (ω-3 PUFA) DHA in protecting against the negative inflammatory effects of repetitive dust exposure in the lung. Dietary manipulation of pulmonary disease risk is an attractive and timely approach given the contribution of an increased ω-6 to ω-3 PUFA ratio to low grade inflammation and chronic disease in the Western diet. To prevent any confounding factors that comes with dietary supplementation of ω-3 PUFA (different sources, purity, dose, and duration), we employed a Fat-1 transgenic mouse model that convert ω-6 PUFA to ω-3 PUFA, leading to a tissue ω-6 to ω-3 PUFA ratio of approximately 1:1. Building on our initial findings, we hypothesized that attaining elevated tissue levels of ω-3 PUFA would attenuate agricultural dust-induced lung inflammation and its resolution. To test this hypothesis, we compared wild-type (WT) and Fat-1 transgenic mice in their response to aqueous extracts of agricultural dust (DE). We also used a soluble epoxide hydrolase inhibitor (sEH) to potentiate the effects of ω-3 PUFA, since sEH inhibitors have been shown to stabilize the anti-inflammatory P450 metabolites derived from both ω-3 and ω-6 PUFA and promote generation of specialized pro-resolving lipid mediators from ω-3 PUFA. Over a three-week period, mice were exposed to a total of 15 intranasal instillations of DE obtained from swine confinement buildings in the Midwest. We observed genotype and sex-specific differences between the WT vs. Fat-1 transgenic mice in response to repetitive dust exposure, where three-way ANOVA revealed significant main effects of treatment, genotype, and sex. Also, Fat-1 transgenic mice displayed reduced lymphoid aggregates in the lung following DE exposure as compared to WT animals exposed to DE, suggesting improved resilience to the DE-induced inflammatory effects. Overall, our data implicate a protective role of ω-3 FA in the lung following repetitive dust exposure.

Respiratory pathologies alter the structure of the lung and impact its mechanics. Mice are widely used in the study of lung pathologies, but there is a lack of fundamental mechanical measurements assessing the interdependent effect of varying inflation volumes and cycling frequency. In this study, the mechanical properties of five male C57BL/6J mice (29-33 weeks of age) lungs were evaluated ex vivo using our custom-designed electromechanical, continuous measure ventilation apparatus. We comprehensively quantify and analyze the effect of loading volumes (0.3, 0.5, 0.7, 0.9 ml) and breathing rates (5, 10, 20 breaths per minute) on pulmonary inflation and deflation mechanical properties. We report means of static compliance between 5.4-16.1 µl/cmH2O, deflation compliance of 5.3-22.2 µl/cmH2O, percent relaxation of 21.7-39.1%, hysteresis of 1.11-7.6 ml•cmH2O, and energy loss of 39-58% for the range of four volumes and three rates tested, along with additional measures. We conclude that inflation volume was found to significantly affect hysteresis, static compliance, starting compliance, top compliance, deflation compliance, and percent relaxation, and cycling rate was found to affect only hysteresis, energy loss, percent relaxation, static compliance and deflation compliance.

Lung cancer is the leading cause of cancer-related deaths worldwide, with increased risk being associated with unresolved or chronic inflammation. Agricultural and livestock workers endure significant exposure to agricultural dusts on a routine basis; however, the chronic inflammatory and carcinogenic effects of these dust exposure is unclear. We have developed a chronic dust exposure model of lung carcinogenesis in which mice were intranasally challenged three times a week for 24 weeks, using an aqueous dust extract (HDE) made from dust collected in swine confinement facilities. We also treated mice with the omega-3-fatty acid lipid mediator, aspirin-triggered resolvin D1 (AT-RvD1) to provide a novel therapeutic strategy for mitigating the inflammatory and carcinogenic effects of HDE. Exposure to HDE resulted in significant immune cell influx into the lungs, enhanced lung tumorigenesis, severe tissue pathogenesis, and a pro-inflammatory and carcinogenic gene signature, relative to saline-exposed mice. AT-RvD1 treatment mitigated the dust-induced inflammatory response but did not protect against HDE + NNK-enhanced tumorigenesis. Our data suggest that chronic HDE exposure induces a significant inflammatory and pro-carcinogenic response, whereas treatment with AT-RvD1 dampens the inflammatory responses, providing a strong argument for the therapeutic use of AT-RvD1 to mitigate chronic inflammation.