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Background and purposeDiabetic nephropathy is a common complications related to high morbidity and mortality in type 2 diabetes. We investigated the action of the dual modulator, PTUPB, a soluble epoxide hydrolase and cyclooxygenase-2 inhibitor against diabetic nephropathy.Experimental approachSixteen-week-old type 2 diabetic and proteinuric obese ZSF1 rats were treated with vehicle, PTUPB or enalapril for 8 weeks. Measurements were made of epoxyeicosatrienoic acids, thromboxane B2 (TBX2 ) and prostaglandin E2 (PGE2 ) in the kidney of these and lean ZSF1 rats along with their blood pressure.Key resultObese ZSF1 rats were diabetic with fivefold higher fasting blood glucose levels and markedly higher HbA1c levels compared with lean ZSF1 rats. PTUPB nor enalapril reduced fasting blood glucose or HbA1c but alleviated the development of diabetic nephropathy. In PTUPB-treated obese ZSF1 rats, glomerular nephrin expression was preserved. Enalapril also alleviated diabetic nephropathy. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with six to sevenfold higher urinary MCP-1 (CCR2) level and renal infiltration of CD-68 positive cells. PTUPB and enalapril significantly reduced urinary MCP-1 levels and renal mRNA expression of cytokines. Both PTUPB and enalapril lowered blood pressure. PTUPB but not enalapril decreased hyperlipidaemia and liver injury in obese ZSF1 rats.Conclusion and implicationsOverall, the dual modulator PTUPB does not treat hyperglycaemia but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidaemia and liver injury in type 2 diabetic rats. Our data further demonstrate that the renal actions of PTUPB are comparable with a current standard diabetic nephropathy treatment.

Background: There is a limited evidence‐base describing clinical features of delirium in youth. What is known is largely extrapolated from studies of adults or samples with heterogeneous etiologies. It is unclear if the symptoms experienced by adolescents differ from those experienced by adults, or the degree to which delirium impacts the ability of adolescents to return to school or work. Objective: To describe delirium symptomatology among adolescents following a severe traumatic brain injury (TBI). Symptoms were compared by adolescent delirium status and across age groups. Delirium and its relationship with adolescent employability 1 year post‐injury was also examined. Design: Exploratory secondary analysis of prospectively collected data. Setting: Free‐standing rehabilitation hospital. Patients: Severely injured TBI Model Systems neurorehabilitation admissions (n = 243; median Glasgow Coma Scale = 7). The sample was divided into three age groups (adolescents, 16–21 years, n = 63; adults 22–49 years, n = 133; older adults ≥50 years, n = 47). Interventions: Not applicable. Measures: We assessed patients using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) diagnostic criteria and the Delirium Rating Scale‐Revised 98 (DRS‐R‐98). The employability item from the Disability Rating Scale was the primary 1‐year outcome. Results: Most items on the DRS‐R‐98 differentiated delirious from non‐delirious adolescents. Only "delusions" differed among age groups. Among adolescents, delirium status 1 month post‐TBI provided acceptable classification of employability prediction 1 year later (area under the curve [AUC]: 0.80, 95% confidence interval [CI]: 0.69–0.91, p <.001). Delirium symptom severity (AUC: 0.86, 95% CI: 0.68–1.03, SE: 0.09; p <.001) and days of post‐traumatic amnesia (AUC: 0.85, 95% CI: 0.68–1.01, SE: 0.08; p <.001) provided excellent prediction of outcomes for TBI patients in delirium. Conclusions: Delirium symptomatology was similar among age groups and useful in differentiating the delirium status within the adolescent TBI group. Delirium and symptom severity at 1 month post‐TBI were highly predictive of poor outcomes. Findings from this study support the utility of DRS‐R‐98 at 1 month post‐injury to inform treatment and planning. [ABSTRACT FROM AUTHOR]

Approximately 10% of US births deliver preterm before 37 weeks of completed gestation. Premature infants are at risk for life‐long debilitating morbidities and death, and spontaneous preterm labour explains 50% of preterm births. In all cases existing treatments are ineffective, and none are FDA approved. The mechanisms that initiate preterm labour are not well understood but may result from dysfunctional regulation of quiescence mechanisms. Human pregnancy is accompanied by large increases in blood flow, and the uterus must enlarge by orders of magnitude to accommodate the growing fetus. This mechanical strain suggests that stretch‐activated channels may constitute a mechanism to explain gestational quiescence. Here we identify for the first time that Piezo1, a mechanosensitive cation channel, is present in the uterine smooth muscle and microvascular endothelium of pregnant myometrium. Piezo is downregulated during preterm labour, and stimulation of myometrial Piezo1 in an organ bath with the agonist Yoda1 relaxes the tissue in a dose‐dependent fashion. Further, stimulation of Piezo1 while inhibiting protein kinase A, AKT, or endothelial nitric oxide synthase mutes the negative inotropic effects of Piezo1 activation, intimating that actions on the myocyte and endothelial nitric oxide signalling contribute to Piezo1‐mediated contractile dynamics. Taken together, these data highlight the importance of stretch‐activated channels in pregnancy maintenance and parturition, and identify Piezo1 as a tocolytic target of interest. Key points: Spontaneous preterm labour is a serious obstetric dilemma without a known cause or effective treatments.Piezo1 is a stretch‐activated channel important to muscle contractile dynamics.Piezo1 is present in the myometrium and is dysregulated in women who experience preterm labour.Activation of Piezo1 by the agonist Yoda1 relaxes the myometrium in a dose‐dependent fashion, indicating that Piezo1 modulation may have therapeutic benefits to treat preterm labour. [ABSTRACT FROM AUTHOR]

Background: Due to random motion of fetuses and maternal respirations, image quality of fetal brain MRIs varies considerably. To address this issue, visual inspection of the images is performed during acquisition phase and after 3D-reconstruction, and the images are re-acquired if they are deemed to be of insufficient quality. However, this process is time-consuming and subjective. Multi-instance (MI) deep learning methods (DLMs) may perform this task automatically.Purpose: To propose an MI count-based DLM (MI-CB-DLM), an MI vote-based DLM (MI-VB-DLM), and an MI feature-embedding DLM (MI-FE-DLM) for automatic assessment of 3D fetal-brain MR image quality. To quantify influence of fetal gestational age (GA) on DLM performance.Study Type: Retrospective.Subjects: Two hundred and seventy-one MR exams from 211 fetuses (mean GA ± SD = 30.9 ± 5.5 weeks).Field Strength/sequence: T2 -weighted single-shot fast spin-echo acquired at 1.5 T.Assessment: The T2 -weighted images were reconstructed in 3D. Then, two fetal neuroradiologists, a clinical neuroscientist, and a fetal MRI technician independently labeled the reconstructed images as 1 or 0 based on image quality (1 = high; 0 = low). These labels were fused and served as ground truth. The proposed DLMs were trained and evaluated using three repeated 10-fold cross-validations (training and validation sets of 244 and 27 scans). To quantify GA influence, this variable was included as an input of the DLMs.Statistical Tests: DLM performance was evaluated using precision, recall, F-score, accuracy, and AUC values.Results: Precision, recall, F-score, accuracy, and AUC averaged over the three cross validations were 0.85 ± 0.01, 0.85 ± 0.01, 0.85 ± 0.01, 0.85 ± 0.01, 0.93 ± 0.01, for MI-CB-DLM (without GA); 0.75 ± 0.03, 0.75 ± 0.03, 0.75 ± 0.03, 0.75 ± 0.03, 0.81 ± 0.03, for MI-VB-DLM (without GA); 0.81 ± 0.01, 0.81 ± 0.01, 0.81 ± 0.01, 0.81 ± 0.01, 0.89 ± 0.01, for MI-FE-DLM (without GA); and 0.86 ± 0.01, 0.86 ± 0.01, 0.86 ± 0.01, 0.86 ± 0.01, 0.93 ± 0.01, for MI-CB-DLM with GA.Data Conclusion: MI-CB-DLM performed better than other DLMs. Including GA as an input of MI-CB-DLM improved its performance. MI-CB-DLM may potentially be used to objectively and rapidly assess fetal MR image quality.Evidence Level: 4 TECHNICAL EFFICACY: Stage 3. [ABSTRACT FROM AUTHOR]

Objective: To determine the association between neighborhood disadvantage (ND) and functional brain development of in utero fetuses., Study Design: We conducted an observational study using Social Vulnerability Index (SVI) scores to assess the impact of ND on a prospectively recruited sample of healthy pregnant women from Washington, DC. Using 79 functional magnetic resonance imaging scans from 68 healthy pregnancies at a mean gestational age of 33.12 weeks, we characterized the overall functional brain network structure using a graph metric approach. We used linear mixed effects models to assess the relationship between SVI and gestational age on 5 graph metrics, adjusting for multiple scans., Results: Exposure to greater ND was associated with less well integrated functional brain networks, as observed by longer characteristic path lengths and diminished global efficiency (GE), as well as diminished small world propensity (SWP). Across gestational ages, however, the association between SVI and network integration diminished to a negligible relationship in the third trimester. Conversely, SWP was significant across pregnancy, but the relationship changed such that there was a negative association with SWP earlier in the second trimester that inverted around the transition to the third trimester to a positive association., Conclusions: These data directly connect ND and altered functional brain maturation in fetuses. Our results suggest that, even before birth, proximity to environmental stressors in the wider neighborhood environment are associated with altered brain development., Competing Interests: Declaration of Competing Interest Supported by the National Institutes of Health, NHLBI R01-HL116585 (C.L.), NICHD T32-HD098066 (K.M.C.), the Canadian Institutes of Health Research MOP-81116 (C.L.), and the A. James & Alice B. Clark Foundation's Parent-Child Health Initiative. The authors report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There is a limited evidence-base describing clinical features of delirium in youth. What is known is largely extrapolated from studies of adults or samples with heterogeneous etiologies. It is unclear if the symptoms experienced by adolescents differ from those experienced by adults, or the degree to which delirium impacts the ability of adolescents to return to school or work., Objective: To describe delirium symptomatology among adolescents following a severe traumatic brain injury (TBI). Symptoms were compared by adolescent delirium status and across age groups. Delirium and its relationship with adolescent employability 1 year post-injury was also examined., Design: Exploratory secondary analysis of prospectively collected data., Setting: Free-standing rehabilitation hospital., Patients: Severely injured TBI Model Systems neurorehabilitation admissions (n = 243; median Glasgow Coma Scale = 7). The sample was divided into three age groups (adolescents, 16-21 years, n = 63; adults 22-49 years, n = 133; older adults ≥50 years, n = 47)., Interventions: Not applicable., Measures: We assessed patients using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria and the Delirium Rating Scale-Revised 98 (DRS-R-98). The employability item from the Disability Rating Scale was the primary 1-year outcome., Results: Most items on the DRS-R-98 differentiated delirious from non-delirious adolescents. Only "delusions" differed among age groups. Among adolescents, delirium status 1 month post-TBI provided acceptable classification of employability prediction 1 year later (area under the curve [AUC]: 0.80, 95% confidence interval [CI]: 0.69-0.91, p < .001). Delirium symptom severity (AUC: 0.86, 95% CI: 0.68-1.03, SE: 0.09; p < .001) and days of post-traumatic amnesia (AUC: 0.85, 95% CI: 0.68-1.01, SE: 0.08; p < .001) provided excellent prediction of outcomes for TBI patients in delirium., Conclusions: Delirium symptomatology was similar among age groups and useful in differentiating the delirium status within the adolescent TBI group. Delirium and symptom severity at 1 month post-TBI were highly predictive of poor outcomes. Findings from this study support the utility of DRS-R-98 at 1 month post-injury to inform treatment and planning., (© 2023 American Academy of Physical Medicine and Rehabilitation.)

Background: Serum lipoproteins, such as high-density lipoproteins (HDL), may influence disease severity in idiopathic pulmonary fibrosis (IPF). Here, we investigated associations between serum lipids and lipoproteins and clinical end-points in IPF., Methods: Clinical data and serum lipids were analysed from a discovery cohort (59 IPF subjects, 56 healthy volunteers) and validated using an independent, multicentre cohort (207 IPF subjects) from the Pulmonary Fibrosis Foundation registry. Associations between lipids and clinical end-points (forced vital capacity, 6-min walk distance, gender age physiology (GAP) index, death or lung transplantation) were examined using Pearson's correlation and multivariable analyses., Results: Serum concentrations of small HDL particles measured using nuclear magnetic resonance spectroscopy (S-HDLP NMR ) correlated negatively with the GAP index in the discovery cohort of IPF subjects. The negative correlation of S-HDLP NMR with GAP index was confirmed in the validation cohort of IPF subjects. Higher levels of S-HDLP NMR were associated with lower odds of death or its competing outcome, lung transplantation (OR 0.9 for each 1-μmol·L -1 increase in S-HDLP NMR , p<0.05), at 1, 2 and 3 years from study entry in a combined cohort of all IPF subjects., Conclusions: Higher serum levels of S-HDLP NMR are negatively correlated with the GAP index, as well as with lower observed mortality or lung transplantation in IPF subjects. These findings support the hypothesis that S-HDLP NMR may modify mortality risk in patients with IPF., Competing Interests: Conflict of interest: A.V. Barochia has nothing to disclose. Conflict of interest: M. Kaler has nothing to disclose. Conflict of interest: N. Weir has nothing to disclose. Conflict of interest: E.M. Gordon has nothing to disclose. Conflict of interest: D.M. Figueroa has nothing to disclose. Conflict of interest: X. Yao has nothing to disclose. Conflict of interest: M. Lemma WoldeHanna has nothing to disclose. Conflict of interest: M. Sampson has nothing to disclose. Conflict of interest: A.T. Remaley has nothing to disclose. Conflict of interest: G. Grant has nothing to disclose. Conflict of interest: S.D. Barnett has nothing to disclose. Conflict of interest: S.D. Nathan is a consultant and is on the speakers’ bureau for Roche-Genentech and Boehringer Ingelheim, and has received research funding from both companies. Conflict of interest: S.J. Levine has nothing to disclose., (The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2021. For commercial reproduction rights and permissions contact permissions@ersnet.org.)