Risk assessment tools for bleeding in patients with unprovoked venous thromboembolism: an analysis of the PLATO-VTE study.

BACKGROUND: Guidelines suggest indefinite anticoagulation after unprovoked venous thromboembolism (VTE) unless the bleeding risk is high, yet there is no consistent guidance on assessing bleeding risk. This study aimed to evaluate the performance of five bleeding risk tools (RIETE, VTE-BLEED, CHAP, VTE-PREDICT, and ABC-bleeding). METHODS: PLATO-VTE, a prospective cohort study, included patients aged ≥40 years with a first unprovoked VTE. Risk estimates were calculated at VTE diagnosis and after 3 months of treatment. Primary outcome was clinically relevant bleeding, as per ISTH criteria, during 24-month follow-up. Discrimination was assessed by the area under the receiver operating characteristic curve (AUROC). Patients were classified as having a 'high-risk' and 'non-high-risk' of bleeding according to predefined thresholds; bleeding risk in both groups was compared by hazard ratios. RESULTS: Of 514 patients, 38 (7.4%) had an on-treatment bleeding. AUROCs were 0.58 (95%CI, 0.48-0.68) for ABC-bleeding, 0.56 (95%CI, 0.46-0.66) for RIETE, 0.53 (95%CI, 0.43-0.64) for CHAP, 0.50 (95%CI, 0.41-0.59) for VTE-BLEED, and 0.50 (95%CI, 0.40-0.60) for VTE-PREDICT. The proportion of high-risk patients ranged from 1.4% with RIETE to 36.9% with VTE-BLEED. The bleeding incidence in the high-risk groups ranged from 0% with RIETE to 13.0% with ABC-bleeding, and in the non-high-risk groups from 7.7% with ABC-bleeding to 9.6% with RIETE. Hazard ratios ranged from 0.93 (95%CI, 0.46-1.9) for VTE-BLEED to 1.67 (95%CI, 0.86-3.2) for ABC-bleeding. Recalibration at 3-month follow-up did not alter the results. CONCLUSIONS: In this cohort, discrimination of currently available bleeding risk tools was poor. These data do not support their use in patients with unprovoked VTE.

Intrapartum exposure to synthetic oxytocin, maternal BMI, and neurodevelopmental outcomes in children within the ECHO consortium.

BACKGROUND: Synthetic oxytocin (sOT) is frequently administered during parturition. Studies have raised concerns that fetal exposure to sOT may be associated with altered brain development and risk of neurodevelopmental disorders. In a large and diverse sample of children with data about intrapartum sOT exposure and subsequent diagnoses of two prevalent neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), we tested the following hypotheses: (1) Intrapartum sOT exposure is associated with increased odds of child ADHD or ASD; (2) associations differ across sex; (3) associations between intrapartum sOT exposure and ADHD or ASD are accentuated in offspring of mothers with pre-pregnancy obesity. METHODS: The study sample comprised 12,503 participants from 44 cohort sites included in the Environmental Influences on Child Health Outcomes (ECHO) consortium. Mixed-effects logistic regression analyses were used to estimate the association between intrapartum sOT exposure and offspring ADHD or ASD (in separate models). Maternal obesity (pre-pregnancy BMI ≥ 30 kg/m2) and child sex were evaluated for effect modification. RESULTS: Intrapartum sOT exposure was present in 48% of participants. sOT exposure was not associated with increased odds of ASD (adjusted odds ratio [aOR] 0.86; 95% confidence interval [CI], 0.71-1.03) or ADHD (aOR 0.89; 95% CI, 0.76-1.04). Associations did not differ by child sex. Among mothers with pre-pregnancy obesity, sOT exposure was associated with lower odds of offspring ADHD (aOR 0.72; 95% CI, 0.55-0.96). No association was found among mothers without obesity (aOR 0.97; 95% CI, 0.80-1.18). CONCLUSIONS: In a large, diverse sample, we found no evidence of an association between intrapartum exposure to sOT and odds of ADHD or ASD in either male or female offspring. Contrary to our hypothesis, among mothers with pre-pregnancy obesity, sOT exposure was associated with lower odds of child ADHD diagnosis.

Metabolomic Analysis and Antiviral Screening of a Marine Algae Library Yield Jobosic Acid (2,5-Dimethyltetradecanoic Acid) as a Selective Inhibitor of SARS-CoV-2.

Current small-molecule-based SARS-CoV-2 treatments have limited global accessibility and pose the risk of inducing viral resistance. Therefore, a marine algae and cyanobacteria extract library was screened for natural products that could inhibit two well-defined and validated COVID-19 drug targets, disruption of the spike protein/ACE-2 interaction and the main protease (Mpro) of SARS-CoV-2. Following initial screening of 86 extracts, we performed an untargeted metabolomic analysis of 16 cyanobacterial extracts. This approach led to the isolation of an unusual saturated fatty acid, jobosic acid (2,5-dimethyltetradecanoic acid, 1). We confirmed that 1 demonstrated selective inhibitory activity toward both viral targets while retaining some activity against the spike-RBD/ACE-2 interaction of the SARS-CoV-2 omicron variant. To initially explore its structure-activity relationship (SAR), the methyl and benzyl ester derivatives of 1 were semisynthetically accessed and demonstrated acute loss of bioactivity in both SARS-CoV-2 biochemical assays. Our efforts have provided copious amounts of a fatty acid natural product that warrants further investigation in terms of SAR, unambiguous determination of its absolute configuration, and understanding of its specific mechanisms of action and binding site toward new therapeutic avenues for SARS-CoV-2 drug development.

Stepping Together for Children After Trauma (ST-CT): Feasibility and Predictors of Outcome of a Parent-led, Therapist Assisted Treatment.

Stepping Together for Children after Trauma (ST-CT) is the first step of the promising intervention Stepped Care CBT for Children after Trauma. In ST-CT, the task of leading treatment is partially shifted to the parents, and the child and parent work together to complete therapeutic tasks from a workbook with therapist supervision. We aimed to investigate the feasibility of ST-CT in Norwegian first line services and explore child factors predicting outcome. Eighty-two children (mean age 9.9 years, 56% girls) participated. Feasibility was defined by treatment completion, reductions of child posttraumatic stress symptoms (PTSS) mid- and post-treatment, and client treatment satisfaction. Predictors included child baseline PTSS, depressive symptoms, posttraumatic cognitions, externalizing symptoms, number of different traumatic events, and type of trauma. Results showed that rates of completion (78.0%) and response (81% of completers/59.8% intention-to-treat) were comparable to previous studies by the ST-CT developer. Overall treatment effect was d = 2.46 and client treatment satisfaction was high (mean score child: 8.3, parent: 9.0, on a scale from 0 - 10). Higher baseline PTSS and depressive symptoms predicted poorer outcome at both mid- and post-treatment, while more posttraumatic cognitions, and exposure to interpersonal trauma predicted poorer outcome at mid-treatment only. These associations were no longer significant in the fully adjusted models. In conclusion, ST-CT shows promise as an effective first line treatment in this new context, with two of three children responding to the treatment. Baseline PTSS, depression, post-traumatic cognitions and type of trauma may be related to outcomes and should be explored further. (Trial registration:  ClinicalTrials.gov Identifier: NCT04073862. Retrospectively registered June 3rd 2019, first patient recruited May 19th 2019).

Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).

Shining a spotlight on the inclusion of disabled participants in clinical trials: a mixed methods study.

BACKGROUND: It is crucial to include a wide range of the population in clinical trials for the outcome to be applicable in real-world settings. Existing literature indicates that under-served groups, including disabled people, have been excluded from participating in clinical trials without justification. Exclusion from clinical trials exacerbates disparities in healthcare and diminishes the benefits for excluded populations. Therefore, this study was conducted to investigate potential obstacles that prevent disabled people from participating in clinical trials in the United Kingdom (UK). METHODS: The study was carried out through an explanatory sequential mixed methods design. The Imperial Clinical Trials Unit devised and implemented an online questionnaire-based survey (with open/closed-ended questions) and an online focus group discussion. The target population were disabled people, family members/carers of disabled people and staff involved in clinical trials, whereupon the sample was recruited by convenience sampling methods via posters and emails through various networks. The Qualtrics XM survey system was used as the host platform for the online survey, and Microsoft Teams was used for an online focus group discussion. The focus group discussion was conducted to gain a deeper understanding of the themes identified from the survey responses. We analysed responses to the survey via descriptive analysis and used thematic analysis to synthesise the free-text answers from the survey and focus group discussion. RESULTS: We received 45 responses to the survey questionnaire and 5 disabled people took part in a focus group discussion. Our findings highlighted the differences between the perspectives of researchers and those "being researched" and different types of barriers experienced by disabled people: opportunity barriers (inadequate recruitment strategy and ambiguous eligibility criteria), awareness barriers (perception of disability) and acceptance/refusal barriers (available support and adjustment, and sharing of trial results). CONCLUSION: Our findings support perspectives drawn from the Ford Framework regarding the need to consider all barriers, not just up to the point of enrolment into trials but also beyond the point of inclusion in clinical trials. We support calls for the introduction of legislation on including disabled people in clinical trials, implementation of industry/community-wide participatory approaches and the development of guidelines, a combined public-private approach.

Randomness impacts the building of specific priors, visual exploration, and perception in object recognition.

Recognising objects is a vital skill on which humans heavily rely to respond quickly and adaptively to their environment. Yet, we lack a full understanding of the role visual information sampling plays in this process, and its relation to the individual's priors. To bridge this gap, the eye-movements of 18 adult participants were recorded during a free-viewing object-recognition task using Dots stimuli1. Participants viewed the stimuli in one of three orders: from most visible to least (Descending), least visible to most (Ascending), or in a randomised order (Random). This dictated the strength of their priors along the experiment. Visibility order influenced the participants' recognition performance and visual exploration. In addition, we found that while orders allowing for stronger priors generally led participants to visually sample more informative locations, this was not the case of Random participants. Indeed, they appeared to behave naïvely, and their use of specific object-related priors was fully impaired, while they maintained the ability to use general, task-related priors to guide their exploration. These findings have important implications for our understanding of perception, which appears to be influenced by complex cognitive processes, even at the basic level of visual sampling during object recognition.

Pregestational fructose-induced metabolic syndrome in Wistar rats causes sexually dimorphic behavioral changes in their offspring.

Metabolic syndrome (MetS), marked by enduring metabolic inflammation, has detrimental effects on cognitive performance and brain structure, influencing behavior. This study aimed to investigate whether maternal MetS could negatively impact the neurodevelopment and metabolism of offspring. To test this hypothesis, 2 months old female Wistar rats were subjected to a 10-week regimen of tap water alone or supplemented with 20% fructose to induce MetS. Dams were mated with healthy males to generate litters: OC (offspring from control dams) and OMetS (offspring from dams with MetS). To isolate prenatal effects, all pups were breastfed by control nurse dams, maintaining a standard diet and water ad libitum until weaning. Behavioral assessments were conducted between postnatal days (PN) 22 and 95, and metabolic parameters were analyzed post-sacrifice on PN100. Results from the elevated plus maze, the open field, and the marble burying tests revealed a heightened anxiety-like phenotype in OMetS females. The novel object recognition test showed that exclusively OMetS males had long-term memory impairment. In the reciprocal social interaction test, OMetS displayed a lower number of social interactions, with a notable increase in "socially inactive" behavior observed exclusively in females. Additionally, in the three-chamber test, social preference and social novelty indexes were found to be lower solely among OMetS females. An increase in visceral fat concomitantly with hypertriglyceridemia was the relevant postmortem metabolic finding in OMetS females. In summary, maternal MetS leads to enduring damage and adverse effects on offspring neurobehavior and metabolism, with notable sexual dimorphism.

Effects of expectation on face perception and its association with expertise.

Perceptual decisions are derived from the combination of priors and sensorial input. While priors are broadly understood to reflect experience/expertise developed over one's lifetime, the role of perceptual expertise at the individual level has seldom been directly explored. Here, we manipulate probabilistic information associated with a high and low expertise category (faces and cars respectively), while assessing individual level of expertise with each category. 67 participants learned the probabilistic association between a color cue and each target category (face/car) in a behavioural categorization task. Neural activity (EEG) was then recorded in a similar paradigm in the same participants featuring the previously learned contingencies without the explicit task. Behaviourally, perception of the higher expertise category (faces) was modulated by expectation. Specifically, we observed facilitatory and interference effects when targets were correctly or incorrectly expected, which were also associated with independently measured individual levels of face expertise. Multivariate pattern analysis of the EEG signal revealed clear effects of expectation from 100 ms post stimulus, with significant decoding of the neural response to expected vs. not stimuli, when viewing identical images. Latency of peak decoding when participants saw faces was directly associated with individual level facilitation effects in the behavioural task. The current results not only provide time sensitive evidence of expectation effects on early perception but highlight the role of higher-level expertise on forming priors.

Performance of two modified two-tier algorithms for the serologic diagnosis of Lyme disease.

We compared the performance of a new modified two-tier testing (MTTT) platform, the Diasorin Liaison chemiluminescent immunoassay (CLIA), to the Zeus enzyme-linked immunoassay (ELISA) MTTT and to Zeus ELISA/Viramed immunoblot standard two-tier testing (STTT) algorithm. Of 537 samples included in this study, 91 (16.9%) were positive or equivocal by one or more screening tests. Among these 91 samples, only 57 samples were concordant positive by first-tier screening tests, and only 19 of 57 were concordant by the three second-tier methods. For IgM results, positive percent agreement (PPA) was 68.1% for Diasorin versus 89.4% for Zeus compared to immunoblot. By contrast, the PPA for IgG for both Diasorin and Zeus was 100%. Using a 2-out-of-3 consensus reference standard, the PPAs for IgM were 75.6%, 97.8%, and 95.6% for Diasorin, Zeus, and immunoblot, respectively. The difference between Zeus MTTT and Diasorin MTTT for IgM detection was significant (P = 0.0094). PPA for both Diasorin and Zeus MTTT IgG assays was 100% but only 65.9% for immunoblot STTT (P = 0.0005). In total, second-tier positive IgM and/or IgG results were reported for 57 samples by Diasorin MTTT, 63 by Zeus MTTT, and 54 by Viramed STTT. While Diasorin CLIA MTTT had a much more rapid, automated, and efficient workflow, Diasorin MTTT was less sensitive for the detection of IgM than Zeus MTTT and STTT including in 5 early Lyme cases that were IgM negative but IgG positive. IMPORTANCE: The laboratory diagnosis of Lyme disease relies upon the detection of antibodies to Borrelia species. Standard two tier testing (STTT) methods rely upon immunoblots which have clinical and technical limitations. Modified two-tier testing (MTTT) methods have recently become available and are being widely adopted. There are limited independent data available assessing the performance of MTTT and STTT methods.

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Transcriptomics- and Genomics-Guided Drug Repurposing for the Treatment of Vesicular Hand Eczema.

Vesicular hand eczema (VHE), a clinical subtype of hand eczema (HE), showed limited responsiveness to alitretinoin, the only approved systemic treatment for severe chronic HE. This emphasizes the need for alternative treatment approaches. Therefore, our study aimed to identify drug repurposing opportunities for VHE using transcriptomics and genomics data. We constructed a gene network by combining 52 differentially expressed genes (DEGs) from a VHE transcriptomics study with 3 quantitative trait locus (QTL) genes associated with HE. Through network analysis, clustering, and functional enrichment analyses, we investigated the underlying biological mechanisms of this network. Next, we leveraged drug-gene interactions and retrieved pharmaco-transcriptomics data from the DrugBank database to identify drug repurposing opportunities for (V)HE. We developed a drug ranking system, primarily based on efficacy, safety, and practical and pricing factors, to select the most promising drug repurposing candidates. Our results revealed that the (V)HE network comprised 78 genes that yielded several biological pathways underlying the disease. The drug-gene interaction search together with pharmaco-transcriptomics lookups revealed 123 unique drug repurposing opportunities. Based on our drug ranking system, our study identified the most promising drug repurposing opportunities (e.g., vitamin D analogues, retinoids, and immunomodulating drugs) that might be effective in treating (V)HE.

Metagenomic sequencing sheds light on microbes putatively associated with pneumonia-related fatalities of white-tailed deer (Odocoileus virginianus).

With emerging infectious disease outbreaks in human, domestic and wild animal populations on the rise, improvements in pathogen characterization and surveillance are paramount for the protection of human and animal health, as well as the conservation of ecologically and economically important wildlife. Genomics offers a range of suitable tools to meet these goals, with metagenomic sequencing facilitating the characterization of whole microbial communities associated with emerging and endemic disease outbreaks. Here, we use metagenomic sequencing in a case-control study to identify microbes in lung tissue associated with newly observed pneumonia-related fatalities in 34 white-tailed deer (Odocoileus virginianus) in Wisconsin, USA. We identified 20 bacterial species that occurred in more than a single individual. Of these, only Clostridium novyi was found to substantially differ (in number of detections) between case and control sample groups; however, this difference was not statistically significant. We also detected several bacterial species associated with pneumonia and/or other diseases in ruminants (Mycoplasma ovipneumoniae, Trueperella pyogenes, Pasteurella multocida, Anaplasma phagocytophilum, Fusobacterium necrophorum); however, these species did not substantially differ between case and control sample groups. On average, we detected a larger number of bacterial species in case samples than controls, supporting the potential role of polymicrobial infections in this system. Importantly, we did not detect DNA of viruses or fungi, suggesting that they are not significantly associated with pneumonia in this system. Together, these results highlight the utility of metagenomic sequencing for identifying disease-associated microbes. This preliminary list of microbes will help inform future research on pneumonia-associated fatalities of white-tailed deer.

Harnessing AI to unmask Copenhagen's invisible air pollutants: A study on three ultrafine particle metrics.

Ultrafine particles (UFPs) are airborne particles with a diameter of less than 100 nm. They are emitted from various sources, such as traffic, combustion, and industrial processes, and can have adverse effects on human health. Long-term mean ambient average particle size (APS) in the UFP range varies over space within cities, with locations near UFP sources having typically smaller APS. Spatial models for lung deposited surface area (LDSA) within urban areas are limited and currently there is no model for APS in any European city. We collected particle number concentration (PNC), LDSA, and APS data over one-year monitoring campaign from May 2021 to May 2022 across 27 locations and estimated annual mean in Copenhagen, Denmark, and obtained additionally annual mean PNC data from 6 state-owned continuous monitors. We developed 94 predictor variables, and machine learning models (random forest and bagged tree) were developed for PNC, LDSA, and APS. The annual mean PNC, LDSA, and APS were, respectively, 5523 pt/cm3, 12.0 µm2/cm3, and 46.1 nm. The final R2 values by random forest (RF) model were 0.93 for PNC, 0.88 for LDSA, and 0.85 for APS. The 10-fold, repeated 10-times cross-validation R2 values were 0.65, 0.67, and 0.60 for PNC, LDSA, and APS, respectively. The root mean square error for final RF models were 296 pt/cm3, 0.48 µm2/cm3, and 1.60 nm for PNC, LDSA, and APS, respectively. Traffic-related variables, such as length of major roads within buffers 100-150 m and distance to streets with various speed limits were amongst the highly-ranked predictors for our models. Overall, our ML models achieved high R2 values and low errors, providing insights into UFP exposure in a European city where average PNC is quite low. These hyperlocal predictions can be used to study health effects of UFPs in the Danish Capital.

FGF21 protects against ischaemia reperfusion injury in normal and fatty livers.

BACKGROUND: Liver ischaemia/reperfusion (I/R) injury, which is an inevitable clinical problem of liver resection, liver transplantation and haemorrhagic shock. Fibroblast growth factor 21 (FGF21) was intimately coupled with multiple metabolic processes and proved to protect against apoptosis and inflammatory response in hepatocytes during hepatic I/R injury. However, the regulatory mechanisms of FGF21 in hepatic I/R injury remains unknown. Therefore, we hypothesize that FGF21 protects hepatic tissues from I/R injury. METHODS: Blood samples were available from haemangiomas patients undergoing hepatectomy and murine liver I/R model and used to further evaluate the serum levels of FGF21 both in humans and mice. We further explored the regulatory mechanisms of FGF21 in murine liver I/R model by using FGF21-knockout mice (FGF21-KO mice) and FGF21-overexpression transgenic mice (FGF21-OE mice) fed a high-fat or ketogenic diet. RESULTS: Our results show that the circulating levels of FGF21 were robustly decreased after liver I/R in both humans and mice. Silencing FGF21 expression with FGF21-KO mice aggravates liver injury at 6 h after 75 min of partial liver ischaemia, while FGF21-OE mice display alleviated hepatic I/R injury and inflammatory response. Compared with chow diet mice, exogenous FGF21 decreases the levels of aminotransferase, histological changes, apoptosis and inflammatory response in hepatic I/R injury treatment mice with a high-fat diet. Meanwhile, ketogenic diet mice are not sensitive to hepatic I/R injury. CONCLUSIONS: The circulating contents of FGF21 are decreased during liver warm I/R injury and exogenous FGF21 exerts hepatoprotective effects on hepatic I/R injury. Thus, FGF21 regulates hepatic I/R injury and may be a key therapeutic target.

Stroke Prevention in Blunt Cerebrovascular Injury: Role of Aspirin 81 mg.

BACKGROUND: The stroke rate in blunt cerebrovascular injury (BCVI) varies from 25% without treatment to less than 8% with antithrombotic therapy. There is no consensus on the optimal management to prevent stroke BCVI. We investigated the efficacy and safety of oral Aspirin (ASA) 81 mg to prevent BCVI-related stroke compared to historically reported stroke rates with ASA 325 mg and heparin. METHODS: A single-center retrospective study included adult trauma patients who received oral ASA 81 mg for BCVI management between 2013 and 2022. Medical records were reviewed for demographic and injury characteristics, imaging findings, treatment-related complications, and outcomes. RESULTS: Eighty-four patients treated with ASA 81 mg for BCVI were identified. The mean age was 41.50 years, and 61.9% were male. The mean Injury Severity Score and Glasgow Coma Scale were 19.82 and 12.12, respectively. A total of 101 vessel injuries were identified, including vertebral artery injuries in 56.4% and carotid artery injuries in 44.6%. Traumatic brain injury was found in 42.9%, and 16.7% of patients had a solid organ injur. Biffl grade I (52.4%) injury was the most common, followed by grade II (37.6%) and grade III (4.9%). ASA 81 mg was started in the first 24 hours in 67.9% of patients, including 20 patients with traumatic brain injury and 8 with solid organ injuries. BCVI-related stroke occurred in 3 (3.5%) patients with Biffl grade II (n = 2) and III (n = 1). ASA-related complications were not identified in any patient. The mean length of stay in the hospital was 10.94 days, and 8 patients died during hospitalization due to complications of polytrauma. Follow-up with computed tomography angiography was performed in 8 (9.5%) patients, which showed improvement in 5 and a stable lesion in 3 at a mean time of 58 days after discharge. CONCLUSIONS: In the absence of clear guidelines regarding appropriate medication, BCVI management should be individualized case-by-case through a multidisciplinary approach. ASA 81 mg is a viable option for BCVI-related stroke prevention compared to the reported stroke rates (2%-8%) with commonly used antithrombotics like heparin and ASA 325 mg. Future prospective studies are needed to provide insight into the safety and efficacy of the current commonly used agent in managing BCVI.