Prognosticating idiopathic pulmonary fibrosis (IPF) is challenging, in part due to a lack of sensitive biomarkers. A recent article in
described how hyperpolarised xenon magnetic resonance ...spectroscopy may quantify regional gas exchange in IPF lungs. In a population of patients with IPF, we find that the xenon signal from red blood cells diminishes relative to the tissue/plasma signal over a 12-month time period, even when the diffusion factor for carbon monoxide is static over the same time period. We conclude that hyperpolarised
Xe MR spectroscopy may be sensitive to short-term changes in interstitial gas diffusion in IPF.
Out-of-hospital cardiac arrest (OHCA) survival varies greatly between communities. The Utstein template was developed and promulgated to improve the comparability of OHCA outcome reports, but it has ...undergone limited empiric validation. We sought to assess how much of the variation in OHCA survival between emergency medical services (EMS) across the globe is explained by differences in the Utstein factors. We also assessed how accurately the Utstein factors predict OHCA survival.
We performed a retrospective analysis of patient-level prospectively collected data from 12 OHCA registries from 12 countries for the period 1 Jan 2006 through 31 Dec 2011. We used generalized linear mixed models to examine the variation in survival between EMS agencies (n=232).
Twelve registries contributed 86,759 cases. Patient arrest characteristics, EMS treatment and patient outcomes varied across registries. Overall survival to hospital discharge was 10% (range, 6% to 22%). Overall survival with Cerebral Performance Category of 1 or 2 (available for 8/12 registries) was 8% (range, 2% to 20%). The area-under-the-curve for the Utstein model was 0.85 (Wald CI: 0.85–0.85). The Utstein factors explained 51% of the EMS agency variation in OHCA survival.
The Utstein factors explained 51% of the variation in survival to hospital discharge among multiple large geographically separate EMS agencies. This suggests that quality improvement and public health efforts should continue to target modifiable Utstein factors to improve OHCA survival. Further study is required to identify the reasons for the variation that is incompletely understood.
Suboptimal adherence to inhaled steroids is common in children with asthma and is associated with poor disease control, reduced quality of life and even death. Previous studies using feedback of ...electronically monitored adherence data have demonstrated improved adherence, but have not demonstrated a significant impact on clinical outcomes. The aim of this study was to determine whether introduction of this approach into routine practice would result in improved clinical outcomes.
Children with asthma aged 6-16 years were randomised to the active intervention consisting of electronic adherence monitoring with daily reminder alarms together with feedback in the clinic regarding their inhaled corticosteroid (ICS) use or to the usual care arm with adherence monitoring alone. All children had poorly controlled asthma at baseline, taking ICS and long-acting β-agonists. Subjects were seen in routine clinics every 3 months for 1 year. The primary outcome was the Asthma Control Questionnaire (ACQ) score. Secondary outcomes included adherence and markers of asthma morbidity.
77 of 90 children completed the study (39 interventions, 38 controls). Adherence in the intervention group was 70% vs 49% in the control group (p≤0.001). There was no significant difference in the change in ACQ, but children in the intervention group required significantly fewer courses of oral steroids (p=0.008) and fewer hospital admissions (p≤0.001).
The results indicate that electronic adherence monitoring with feedback is likely to be of significant benefit in the routine management of poorly controlled asthmatic subjects.
NCT02451709; pre-result.
Respiratory diseases are leading causes of mortality and morbidity worldwide. Pulmonary imaging is an essential component of the diagnosis, treatment planning, monitoring, and treatment assessment of ...respiratory diseases. Insights into numerous pulmonary pathologies can be gleaned from functional lung MRI techniques. These include hyperpolarized gas ventilation MRI, which enables visualization and quantification of regional lung ventilation with high spatial resolution. Segmentation of the ventilated lung is required to calculate clinically relevant biomarkers. Recent research in deep learning (DL) has shown promising results for numerous segmentation problems. Here, we evaluate several 3D convolutional neural networks to segment ventilated lung regions on hyperpolarized gas MRI scans. The dataset consists of 759 helium-3 (
He) or xenon-129 (
Xe) volumetric scans and corresponding expert segmentations from 341 healthy subjects and patients with a wide range of pathologies. We evaluated segmentation performance for several DL experimental methods via overlap, distance and error metrics and compared them to conventional segmentation methods, namely, spatial fuzzy c-means (SFCM) and K-means clustering. We observed that training on combined
He and
Xe MRI scans using a 3D nn-UNet outperformed other DL methods, achieving a mean ± SD Dice coefficient of 0.963 ± 0.018, average boundary Hausdorff distance of 1.505 ± 0.969 mm, Hausdorff 95th percentile of 5.754 ± 6.621 mm and relative error of 0.075 ± 0.039. Moreover, limited differences in performance were observed between
Xe and
He scans in the testing set. Combined training on
Xe and
He yielded statistically significant improvements over the conventional methods (p < 0.0001). In addition, we observed very strong correlation and agreement between DL and expert segmentations, with Pearson correlation of 0.99 (p < 0.0001) and Bland-Altman bias of - 0.8%. The DL approach evaluated provides accurate, robust and rapid segmentations of ventilated lung regions and successfully excludes non-lung regions such as the airways and artefacts. This approach is expected to eliminate the need for, or significantly reduce, subsequent time-consuming manual editing.
Optimization of a Series of RIPK2 PROTACs Miah, Afjal H; Smith, Ian E. D; Rackham, Mark ...
Journal of medicinal chemistry,
09/2021, Letnik:
64, Številka:
17
Journal Article
Recenzirano
Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit ...members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.
Functional lung imaging modalities such as hyperpolarized gas MRI ventilation enable visualization and quantification of regional lung ventilation; however, these techniques require specialized ...equipment and exogenous contrast, limiting clinical adoption. Physiologically-informed techniques to map proton (
H)-MRI ventilation have been proposed. These approaches have demonstrated moderate correlation with hyperpolarized gas MRI. Recently, deep learning (DL) has been used for image synthesis applications, including functional lung image synthesis. Here, we propose a 3D multi-channel convolutional neural network that employs physiologically-informed ventilation mapping and multi-inflation structural
H-MRI to synthesize 3D ventilation surrogates (PhysVENeT). The dataset comprised paired inspiratory and expiratory
H-MRI scans and corresponding hyperpolarized gas MRI scans from 170 participants with various pulmonary pathologies. We performed fivefold cross-validation on 150 of these participants and used 20 participants with a previously unseen pathology (post COVID-19) for external validation. Synthetic ventilation surrogates were evaluated using voxel-wise correlation and structural similarity metrics; the proposed PhysVENeT framework significantly outperformed conventional
H-MRI ventilation mapping and other DL approaches which did not utilize structural imaging and ventilation mapping. PhysVENeT can accurately reflect ventilation defects and exhibits minimal overfitting on external validation data compared to DL approaches that do not integrate physiologically-informed mapping.
Out-of-hospital cardiac arrest is a global public health issue experienced by ≈3.8 million people annually. Only 8% to 12% survive to hospital discharge. Early defibrillation of shockable rhythms is ...associated with improved survival, but ensuring timely access to defibrillators has been a significant challenge. To date, the development of public-access defibrillation programs, involving the deployment of automated external defibrillators into the public space, has been the main strategy to address this challenge. Public-access defibrillator programs have been associated with improved outcomes for out-of-hospital cardiac arrest; however, the devices are used in <3% of episodes of out-of-hospital cardiac arrest. This scientific statement was commissioned by the International Liaison Committee on Resuscitation with 3 objectives: (1) identify known barriers to public-access defibrillator use and early defibrillation, (2) discuss established and novel strategies to address those barriers, and (3) identify high-priority knowledge gaps for future research to address. The writing group undertook systematic searches of the literature to inform this statement. Innovative strategies were identified that relate to enhanced public outreach, behavior change approaches, optimization of static public-access defibrillator deployment and housing, evolved automated external defibrillator technology and functionality, improved integration of public-access defibrillation with existing emergency dispatch protocols, and exploration of novel automated external defibrillator delivery vectors. We provide evidence- and consensus-based policy suggestions to enhance public-access defibrillation and guidance for future research in this area.
Purpose
To characterize the dependence of Xe‐MRI gas transfer metrics upon age, sex, and lung volume in a group of healthy volunteers.
Methods
Sixty‐five subjects with no history of chronic lung ...disease were assessed with 129Xe‐MRI using a four‐echo 3D radial spectroscopic imaging sequence and a dose of xenon titrated according to subject height that was inhaled from a lung volume of functional residual capacity (FRC). Imaging was repeated in 34 subjects at total lung capacity (TLC). Regional maps of the fractions of dissolved xenon in red blood cells (RBC), membrane (M), and airspace (Gas) were acquired at an isotropic resolution of 2 cm, from which global averages of the ratios RBC:M, RBC:Gas, and M:Gas were computed.
Results
Data from 26 males and 36 females with a median age of 43 y (range: 20–69 y) were of sufficient quality to analyze. Age (p = 0.0006) and sex (p < 0.0001) were significant predictors for RBC:M, and a linear regression showed higher values and steeper decline in males: RBC:M(Males) = −0.00362 × Age + 0.60 (p = 0.01, R2 = 0.25); RBC:M(Females) = −0.00170 × Age + 0.44 (p = 0.02, R2 = 0.15). Similarly, age and sex were significant predictors for RBC:Gas but not for M:Gas. RBC:M, M:Gas and RBC:Gas were significantly lower at TLC than at FRC (plus inhaled volume), with an average 9%, 30% and 35% decrease, respectively.
Conclusion
Expected age and sex dependence of pulmonary function concurs with 129Xe RBC:M imaging results, demonstrating that these variables must be considered when reporting Xe‐MRI metrics. Xenon doses and breathing maneuvers should be controlled due to the strong dependence of Xe‐MRI metrics upon lung volume.
Identifying mechanisms underlying the intergenerational transmission of risk for attention-deficit/hyperactivity disorder (ADHD) traits can inform interventions and provide insights into the role of ...parents in shaping their children's outcomes. We investigated whether genetic transmission and genetic nurture (environmentally mediated effects) underlie associations between polygenic scores indexing parental risk and protective factors and their offspring's ADHD traits. This birth cohort study included 19,506 genotyped mother-father-offspring trios from the Norwegian Mother, Father and Child Cohort Study. Polygenic scores were calculated for parental factors previously associated with ADHD, including psychopathology, substance use, neuroticism, educational attainment, and cognitive performance. Mothers reported on their 8-year-old children's ADHD traits (n = 9,454 children) using the Parent/Teacher Rating Scale for Disruptive Behaviour Disorders. We found that associations between ADHD maternal and paternal polygenic scores and child ADHD traits decreased significantly when adjusting for the child polygenic score (p
= 9.95 × 10
for maternal and p
= 1.48 × 10
for paternal estimates), suggesting genetic transmission of ADHD risk. Similar patterns suggesting genetic transmission of risk were observed for smoking, educational attainment, and cognition. The maternal polygenic score for neuroticism remained associated with children's ADHD ratings even after adjusting for the child polygenic score, indicating genetic nurture. There was no robust evidence of genetic nurture for other parental factors. Our findings indicate that the intergenerational transmission of risk for ADHD traits is largely explained by the transmission of genetic variants from parents to offspring rather than by genetic nurture. Observational associations between parental factors and childhood ADHD outcomes should not be interpreted as evidence for predominantly environmentally mediated effects.
Several maternal exposures during pregnancy are considered predisposing factors for offspring neurodevelopmental conditions. However, many of these exposures may be noncausal and biased by maternal ...genetic liability.
To assess whether pregnancy-related predisposing factors for offspring neurodevelopmental conditions are associated with maternal genetic liability for attention-deficit/hyperactivity disorder (ADHD), autism, and schizophrenia and to compare associations for maternal genetic liability with those for paternal genetic liability, which could indicate that paternal exposures are not suitable negative controls for maternal exposures.
The Norwegian Mother, Father and Child Cohort Study (MoBa) is a population-based pregnancy cohort that recruited parents from June 1999 to December 2008. Polygenic scores (PGS) for ADHD, autism, and schizophrenia were derived in mothers and fathers. The associations between maternal PGS and 37 pregnancy-related measures were estimated, and these results were compared with those from paternal PGS predicting paternal measures during the mother's pregnancy. Analysis took place between March 2021 and March 2022.
PGS for ADHD, autism, and schizophrenia, calculated (using discovery effect size estimates and threshold of P < .05) from the largest available genome-wide association studies.
Self-reported pregnancy-related measures capturing lifestyle behaviors, metabolism, infectious and autoimmune diseases, other physical health conditions, and medication use.
Data were available for up to 14 539 mothers (mean SD age, 30.00 4.45 years) and 14 897 fathers (mean SD age, 32.46 5.13 years) of European ancestry. Modest but robust associations were observed between specific pregnancy-related measures and maternal PGS, including ADHD PGS with asthma (odds ratio OR, 1.15 95% CI, 1.06-1.25), smoking (OR, 1.26 95% CI, 1.19-1.33), prepregnancy body mass index (β, 0.25 95% CI, 0.18-0.31), pregnancy weight gain (β, 0.20 95% CI, 0.10-0.30), taking folate (OR, 0.92 95% CI, 0.88-0.96), and not taking supplements (OR, 1.09 95% CI, 1.04-1.14). Schizophrenia PGS was associated with coffee consumption (OR, 1.09 95% CI, 1.05-1.12), smoking (OR, 1.12 95% CI, 1.06-1.19), prepregnancy body mass index (β, -0.18 95% CI, -0.25 to -0.11), and pregnancy weight gain (β, 0.17 95% CI, 0.07-0.27). All 3 PGSs associated with symptoms of depression/anxiety (ADHD: OR, 1.15 95% CI, 1.09-1.22; autism: OR, 1.13 95% CI, 1.06-1.19; schizophrenia: OR, 1.13 95% CI, 1.07-1.20). Associations were largely consistent for maternal and paternal PGS, except ADHD PGS and smoking (fathers: OR, 1.13 95% CI, 1.09-1.17).
In this study, genetic liability to neurodevelopmental conditions that is passed from mothers to children was associated with several pregnancy-related factors and may therefore confound associations between these pregnancy-related factors and offspring neurodevelopment that have previously been thought to be causal. It is crucial that future study designs account for genetic confounding to obtain valid causal inferences so that accurate advice can be given to pregnant individuals.
PDF
