Introduction: Although IgA nephropathy (IgAN) is the most common recurrent glomerulonephritis encountered in the kidney allograft, the clinical and immunogenetic characteristics remain poorly ...understood. We sought to study determinants and prognosis of recurrent IgAN with special focus on human leukocyte antigens (HLAs). Materials and Methods: Between 2005 and 2019, we identified 282 transplanted patients with failure secondary to IgAN from 2 North American and 1 European Medical Centers, including 80 with recurrent IgAN and 202 without recurrence. The prevalence of HLAs was compared to external healthy controls of European ancestry (n = 15,740). Graft survival was assessed by the Kaplan-Meier method and log rank test. Cox proportional hazards were used for multivariable analyses. Results: Compared to external controls of European ancestry, kidney transplant recipients of European ancestry with kidney failure secondary to IgAN had higher frequency of HLA-DQ5 (42% vs. 30%, OR = 1.68, p = 0.002) and lower frequency of HLA-DR15 (15% vs. 28%, OR = 0.46, p < 0.001) and HLA-DQ6 (32% vs. 45%, OR = 0.59, p = 0.003); however, the frequency of these HLAs were similar in recurrent versus nonrecurring IgAN. Younger recipient age at transplantation was an independent predictor of recurrence. HLA matching was an independent predictor for recurrent IgAN only in recipients of living-related but not deceased or living-unrelated transplants. Recurrent IgAN was an independent predictor of allograft failure, along with acute rejection. In patients with recurrent IgAN, serum creatinine at biopsy, degree of proteinuria, and concurrent acute rejection were associated with inferior allograft survival. Conclusion: Recurrent IgAN negatively affects allograft survival. Younger recipient age at transplantation is an independent predictor of recurrent IgAN, while the presence of HLAs associated with IgAN in the native kidney and HLA matching in recipients of deceased or living-unrelated transplants are not.
Noninvasive Risk Assessment Early After a Myocardial Infarction: The REFINE Study Derek V. Exner, Katherine M. Kavanagh, Michael P. Slawnych, L. Brent Mitchell, Darlene Ramadan, Sandeep G. Aggarwal, ...Catherine Noullett, Allie Van Schaik, Ryan T. Mitchell, Mariko A. Shibata, Sajad Gulamhussein, James McMeekin, Wayne Tymchak, Gregory Schnell, Anne M. Gillis, Robert S. Sheldon, Gordon H. Fick, Henry J. Duff, for the REFINE Investigators A group of 322 patients underwent testing at 2 to 4 weeks and 10 to 14 weeks after myocardial infarction (MI). Only the assessment at 10 to 14 weeks after MI reliably identified patients at risk of the primary outcome (cardiac death or cardiac arrest). The combination of impaired heart rate turbulence, abnormal exercise repolarization alternans, and an ejection fraction < 0.50 beyond 8 weeks after MI identified patients with over a 5-fold higher risk. Most patients at risk were identified, with good positive (23%) and negative (95%) predictive accuracy. This approach reliably identifies patients at risk of serious events when measured early after MI.
Despite the age old warnings against the use of alcohol during pregnancy, and the abundance of scientific research that links Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE) with ...prenatal maternal alcohol ingestion, FAS/FAE remains one of the leading causes of birth defects and mental retardation. It is critical to explore the reasons why women may choose to drink alcohol during their pregnancies to identify areas which may direct interventions and future research. A descriptive cross-sectional survey was completed using Beeker's Health Belief Model (1974) as a guide to exploring the phenomena of alcohol consumption during pregnancy. A researcher designed self-reporting questionnaire that incorporated previously used tools and open-ended questions was used to gather information from the 117 pregnant study participants regarding their knowledge, beliefs, behaviours, and decision making related to alcohol consumption during pregnancy. A small number of study participants continued to drink duringtheir pregnancy. They tended to be older, Caucasian, more educated, in a higher family income bracket, and with slightly lower knowledge scores. In general, the study sample possessed a high knowledge level and high levels of perceived susceptibility and severity to FAS/FAE. The most common benefit cited by participants for abstaining from alcohol during pregnancy was for health reasons, especially related to the baby. The most common barrier to abstaining was related to alcohol being an enjoyable part of the woman's lifestyle. Recommendations are made for health care education, practice, future research, and refinement of the research questionnaire.
Emotion dysregulation increases the risk of depression, anxiety, and substance use disorders. Music can help regulate emotions, and mobile phones provide constant access to it. The Music eScape ...mobile app teaches young people how to identify and manage emotions using music.
This study aimed to examine the effects of using Music eScape on emotion regulation, distress, and well-being at 1, 2, 3, and 6 months. Moderators of outcomes and user ratings of app quality were also examined.
A randomized controlled trial compared immediate versus 1-month delayed access to Music eScape in 169 young people (aged 16 to 25 years) with at least mild levels of mental distress (Kessler 10 score>17).
No significant differences between immediate and delayed groups on emotion regulation, distress, or well-being were found at 1 month. Both groups achieved significant improvements in 5 of the 6 emotion regulation skills, mental distress, and well-being at 2, 3, and 6 months. Unhealthy music use moderated improvements on 3 emotion regulation skills. Users gave the app a high mean quality rating (mean 3.8 SD 0.6) out of 5.
Music eScape has the potential to provide a highly accessible way of improving young people's emotion regulation skills, but further testing is required to determine its efficacy. Targeting unhealthy music use in distressed young people may improve their emotion regulation skills.
Australian New Zealand Clinical Trials Registry ACTRN12615000051549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365974.
Phthalate exposure is widespread, and studies suggest an adverse relationship with asthma morbidity, including some support for oxidative stress as an underlying pathophysiological mechanism. Urinary ...phthalate metabolites have been associated with biomarkers of oxidative stress, but data are few in children diagnosed with asthma. We used participant data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine longitudinal relationships between phthalates and oxidative stress in a cohort of Latino children with asthma residing in an agricultural community. We used linear mixed-effects models to estimate associations between 11 urinary phthalate metabolites (and one summed measure of di-2-ethylhexyl phthalate (DEHP) metabolites, ∑DEHP) and two urinary biomarkers of oxidative stress: a biomarker of lipid peroxidation via measure of 8-isoprostane and a biomarker of DNA/RNA oxidative damage via combined measure of 8-hydroxydeoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), and 8-hydroxyguanine. Seventy-nine participants provided 281 observations. In covariate-adjusted models, we observed significant positive relationships between all phthalate metabolites and 8-isoprostane, effect sizes ranging from a 9.3 % (95 % CI: 4.2 %–14.7 %) increase in 8-isoprostane for each 100 % increase (i.e., doubling) of mono-(carboxy-isooctyl) phthalate (MCIOP), to a 21.0 % (95 % CI: 14.3 %–28.2 %) increase in 8-isoprostane for each doubling of mono-n-butyl phthalate (MNBP). For each doubling of mono-(carboxy-isononyl) phthalate (MCINP) and mono-ethyl phthalate (MEP), the DNA/RNA oxidative damage biomarker increased by 6.0 % (95 % CI: 0.2 %–12.2 %) and 6.5 % (95 % CI: 1.4 %–11.9 %), respectively. In conclusion, we provide unique data suggesting phthalate exposure is positively associated with oxidative stress in children with asthma. Our repeat measures provide novel identification of a consistent effect of phthalates on oxidative stress in children with asthma via lipid peroxidation. Confirmation in future studies of children with asthma is needed to enhance understanding of the role of phthalates in childhood asthma morbidity.
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•Phthalates are linked to childhood asthma and oxidative stress (OS).•We estimated longitudinal associations of phthalates and OS in youth with asthma.•Positive associations were observed with two distinct measures of oxidative stress.•Strongest associations were observed with 8-isoprostane.•These data motivate further study of phthalate exposure's link to asthma via OS.
ABSTRACT
Background and Aims
Recent meta‐analyses of motivational interviewing (MI) for reducing risky alcohol use in young people have reported modest effects. Few studies have targeted individual ...patient factors to increase MI effectiveness. This study determined if MI enhanced with individualised personality‐specific coping skills training (QuikFix) was more efficacious than standard MI or an assessment feedback/information (AF/I) control among young people with alcohol‐related injuries or illnesses.
Design and Setting
Single‐centre, single‐blind, three‐group superiority randomized controlled trial with 1‐, 3‐, 6‐ and 12‐months follow‐ups. Telephone intervention, Brisbane, Australia.
Participants
A total of 398 young people (16–25 years; M age = 20.30 years, SD = 2.12; 54% female) with alcohol‐related injuries and/or illnesses were recruited from an emergency department (ED) or rest/recovery service (RRS).
Measures
The primary outcome was total standard (10 g ethanol) drinks in the past month (Timeline Follow back TLFB) at 12 months (primary time point). Secondary outcomes were total drinking days and standard drinks per drinking day (TLFB) in the past month and the frequency of alcohol‐related problems in the past 3 months (Rutgers Alcohol Problem Index).
Interventions
Young people were randomized to two sessions of QuikFix enhanced with individualised personality‐specific coping skills training (n = 132), two sessions of MI (n = 136) or one session of AF/I (n = 130), all delivered by telehealth.
Findings
QuikFix resulted in greater reductions (all P < 0.0017) in the primary outcome of total standard drinks (M = 19.50, CI 99.75% = 11.31, 27.68) than both MI (M = 32.61, CI 99.75% = 24.82, 40.40; Cohen's D = 0.40) and AF/I (M = 34.12, CI 99.75% = 26.59, 41.65; D = 0.45) at 12 months (retention n = 324/398, 81%). QuikFix had greater reductions on drinking days (M = 3.16, CI 99.75% = 2.37, 3.96) than both MI (M = 4.53, CI 99.75% = 3.57, 5.48;D = 0.38) and AF/I (M = 4.69, CI 99.75% = 3.73, 5.65;D = 0.42) and fewer drinks per drinking day (M = 5.02, CI 99.75% = 3.71, 6.33) than AF/I (M = 7.15, CI 99.75% = 5.93, 8.38;D = 0.47) at 12 months.
Conclusions
Young people with alcohol‐related injuries and/or illnesses who attended ED and rest/recovery services and received an individualised personality‐specific coping skills training intervention (QuikFix) had greater reductions in the amount of alcohol consumed at 12 months compared with those who received motivational interviewing or an assessment feedback/information intervention.
Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. ...Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.
Phthalates are a class of widely used synthetic chemicals found in commonly used materials and products. Epidemiological studies suggest phthalate exposure is associated with asthma outcomes, though ...most studies have not investigated phthalates as triggers of exacerbations in children diagnosed with asthma. This study used data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine relationships between phthalate exposure and outcomes related to childhood asthma exacerbation. We used measures of phthalate metabolites and respiratory health measures including fractional exhaled nitric oxide (FENO), the Asthma Control Test (ACT), caregiver report of symptoms, and urinary leukotriene E4 (uLTE4) to estimate longitudinal associations using mixed effects models, adjusted for covariates. For 100% (i.e., doubling) increases in mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-2-ethylhexyl phthalate (MEHP), and mono-ethyl phthalate (MEP), concentrations of FENO increased by 8.7% (95% CI: 0.7–17.3), 7.2% (95% CI: 0.0–14.9), and 6.4% (95% CI: 0.0–13.3), respectively. All phthalate metabolites demonstrated associations with uLTE4, effect sizes ranging from an 8.7% increase in uLTE4 (95% CI: 4.3–12.5) for a 100% increase in MEHP to an 18.1% increase in uLTE4 (95% CI: 13.3–23.1) for a 100% increase in MNBP. In models of caregiver report of symptoms, no phthalate metabolites were significantly associated in primary models. No phthalate metabolites were associated with standardized ACT score. Our results suggest urinary phthalate metabolites are significant predictors of inflammatory biomarkers related to asthma exacerbation in children but not child and caregiver report of airway symptomatology.
•Phthalates are linked to asthma outcomes, but few studies focus on children diagnosed with asthma.•This study in a rural Latinx child cohort assessed phthalate exposure and asthma outcomes over time.•Urinary phthalate metabolites were associated with biomarkers of inflammation related to asthma.•Phthalates were not associated with symptom report or the Asthma Control Test.
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