To investigate how glucose abnormalities correlate with brain function on amplitude-integrated electroencephalography (aEEG) in infants with neonatal encephalopathy.
Neonates born at full term with ...encephalopathy were enrolled within 6 hours of birth in a prospective cohort study at a pediatric academic referral hospital. Continuous interstitial glucose monitors and aEEG were placed soon after birth and continued for 3 days. Episodes of hypoglycemia (≤50 mg/dL; ≤2.8 mmol/L) and hyperglycemia (>144 mg/dL; >8.0 mmol/L) were identified. aEEG was classified in 6-hour epochs for 3 domains (background, sleep–wake cycling, electrographic seizures). Generalized estimating equations assessed the relationship of hypo- or hyperglycemia with aEEG findings, adjusting for clinical markers of hypoxia-ischemia (Apgar scores, umbilical artery pH, and base deficit).
Forty-five infants (gestational age 39.5 ± 1.4 weeks) were included (24 males). During aEEG monitoring, 16 episodes of hypoglycemia were detected (9 infants, median duration 77.5, maximum 220 minutes) and 18 episodes of hyperglycemia (13 infants, median duration 237.5, maximum 3125 minutes). Epochs of hypoglycemia were not associated with aEEG changes. Compared with epochs of normoglycemia, epochs of hyperglycemia were associated with worse aEEG background scores (B 1.120, 95% CI 0.501-1.738, P < .001), less sleep–wake cycling (B 0.587, 95% CI 0.417-0.757, P < .001) and more electrographic seizures (B 0.433, 95% CI 0.185-0.681, P = .001), after adjusting for hypoxia–ischemia severity.
In neonates with encephalopathy, epochs of hyperglycemia were temporally associated with worse global brain function and seizures, even after we adjusted for hypoxia–ischemia severity. Whether hyperglycemia causes neuronal injury or is simply a marker of severe brain injury requires further study.
The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors ...that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
Infection is a risk factor for adverse neurodevelopmental outcome in preterm newborns. Our objective was to characterize the association of postnatal infection with adverse microstructural and ...metabolic brain development in premature newborns.
In 34/117 newborns studied, clinical signs were accompanied by positive cultures whereas 17 had clinical signs of sepsis alone. White matter injury (WMI) was identified in 34 newborns. In multivariate regression models, infected newborns had brain imaging measures indicative of delayed brain development: lower N-acetylaspartate/choline, elevated average diffusivity (D(AV)), and decreased white matter fractional anisotropy. These widespread brain abnormalities were found in both newborns with positive-culture infection and in those with clinical infection.
These findings suggest that postnatal infection, even without a positive culture, is an important risk factor for widespread abnormalities in brain development. These abnormalities extend beyond brain injuries apparent with conventional magnetic resonance injury (MRI).
117 preterm newborns (24-32 wk gestation) were studied prospectively at a median of 32.0 and 40.3 wk ostmenstrual age with MRI (WMI, hemorrhage), magnetic resonance (MR) spectroscopy (metabolism), and diffusion tensor imaging (microstructure). Newborns were categorized as having "no infection," "clinical infection," or "positive-culture infection." We compared brain injuries as well as metabolic and microstructural development across these infection groups.
BACKGROUND: PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, ...the possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. METHOD: We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1 MyHC6 ). RESULTS: PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism and resulting glycolytic ATP production, with a concurrent decrease in oxidative phosphorylation, both in vivo and in vitro. In vitro, treatment of H9c2 (H9c2 rat myoblast cell line) cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knockdown of PANX1. To investigate nonischemic heart failure and the preceding cardiac hypertrophy, we administered isoproterenol, and we demonstrated that Panx1 MyHC6 mice were protected from systolic and diastolic left ventricle volume increases as a result of cardiomyocyte hypertrophy. Moreover, we found that Panx1 MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45 + ), particularly neutrophils (CD11b + integrin subunit alpha M, Ly6g + lymphocyte antigen 6 family member G), to the myocardium. CONCLUSIONS: Together, these data demonstrate that PANX1 deficiency in cardiomyocytes increases glycolytic metabolism and protects against cardiac hypertrophy in nonischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in patients with heart failure.
•Cohort study of neonatal encephalopathy using continuous glucose monitoring.•Higher glucose on day 1 associated with widespread changes in brain microstructure.•Lower glucose not associated with ...brain microstructural changes.•No changes in MR spectroscopy found related to higher or lower glucose.
To identify how alterations in glucose levels are associated with regional brain injury in neonatal encephalopathy.
This was a prospective cohort study of 102 newborns with neonatal encephalopathy, with continuous glucose monitoring for 72 h. 97 (95%) completed 72 h of therapeutic hypothermia. Brain imaging around day 5 of life included diffusion tensor imaging and MR spectroscopy. Regions of interest were placed for both DTI and MR spectroscopy, and tractography of the optic radiation and corticospinal tract were evaluated. Linear regression models related each MR metric with minimum and maximum glucose values during each day of life, adjusting for 5-minute Apgar scores and umbilical artery pH.
Higher maximum glucose levels on the first day of life were associated with widespread changes in mean diffusivity in the anterior and posterior white matter, splenium of the corpus callosum, lentiform nucleus, pulvinar nucleus of the thalamus, posterior limb of the internal capsule, and optic radiations, thus including regions traditionally associated with hypoxia–ischemia or hypoglycemia. No associations were found between lower minimum glucose levels and DTI changes in any regions tested, or between glucose levels and MR spectroscopy.
In this cohort of neonatal encephalopathy with therapeutic hypothermia, higher maximal glucose on the first day of life was associated with widespread microstructural changes, but lower minimum glucose levels were not associated with changes in any of the regions tested. Long-term follow-up will determine if imaging findings translate to long-term outcomes.
Objective
Holographic Memory Resolution® (HMR®), a mind‐based therapy, has been used for decades as a nonpharmacologic intervention for trauma imprinting to alleviate depression, anxiety, pain, and ...post‐traumatic stress disorder (PTSD). No clinical studies were found examining the use of HMR®. This study examined the feasibility and preliminary efficacy of administering HMR® to individuals experiencing chronic pain and related biopsychosocial symptoms.
Methods
A feasibility, mixed‐methods study was conducted between October 2021 and July 2022 and included four HMR® sessions over 1–12 weeks. A convenience sample was comprised of 60 adults suffering from chronic physical or emotional pain of 4+ (0–10 scale) over 6+ months at two clinics in the U.S. Baseline and subsequent surveys after sessions 2, 3, and 4 assessed symptom response. Symptoms were longitudinally measured via self‐report of depression, anxiety, somatic symptom burden, PTSD, and vitality.
Results
73% completed all four sessions, demonstrating feasibility. Ages ranged from 19 to 80 years, 85% were female, and 87% were Caucasian. 52% reported high risk for toxic stress. Four symptoms decreased significantly: depression (p = 0.05), anxiety (p = 0.03), symptom burden (p < 0.01) and PTSD symptoms (p = 0.01); vitality improved.
Conclusions
HMR® may be a feasible intervention to address chronic pain and accompanying biopsychosocial symptoms; a randomized controlled trial is the next step to measure efficacy. Unlike other mind‐based therapies, HMR® participants use their own internal language for identification and resolution of the pain. The trauma imprinting can then be gently addressed, and the memory‐based components of pain resolved or reduced, which empowers participants to improve their well‐being.
Trial registration
ClinicalTrials.gov Identifier: NCT05001399.
HIGHLIGHTS
While used for decades, this is the first trial reported in the scientific literature to examine the use of Holographic Memory Resolution® (HMR®) in any population.
HMR® is a feasible intervention to address chronic pain and accompanying biopsychosocial symptoms.
HMR® was found to significantly decrease depression, anxiety, symptom burden, and post‐traumatic stress disorder symptoms in patients experiencing chronic pain.
POCUS is a growing field in medical education, and an imaging modality ideal for children given the lack of ionizing radiation, ease of use, and good tolerability. A 2019 literature review revealed ...that no US pediatric residency programs integrated obligatory POCUS curricula. Our objective was to provide a formalized POCUS curriculum over multiple years, and to retrospectively assess improvement in resident skills and comfort.
During intern year, pediatric residents received didactics and hands-on scanning opportunities in basic POCUS applications. Their evaluation tools included pre- and post-surveys and tests, and a final performance exam. In the second and third years of residency, all participants were required to complete 8 hours per year of POCUS content review and additional hands-on training. An optional third-year curriculum was offered to interested residents as career-focused education elective time.
Our curriculum introduced POCUS topics such as basic and advanced cardiac, lung, skin/soft tissues and procedural based ultrasound to all pediatric residents. Among first-year residents, application-specific results showed POCUS comfort level improved by 61-90%. Completed evaluations demonstrated improvement in their ability to recognize and interpret POCUS images. Second- and third-year residents reported educational effectiveness that was rated 3.9 on a 4-point Likert scale. Four third-year residents took part in the optional POCUS elective, and all reported a change in their practice with increased POCUS incorporation.
Our longitudinal pediatric residency POCUS curriculum is feasible to integrate into residency training and exhibits early success.
Preterm birth has a dramatic impact on polyunsaturated fatty acid exposures for the developing brain. This study examined the association between postnatal fatty acid levels and measures of brain ...injury and development, as well as outcomes.
A cohort of 60 preterm newborns (24-32 wk gestational age) was assessed using early and near-term magnetic resonance imaging (MRI) studies. Red blood cell fatty acid composition was analyzed coordinated with each scan. Outcome at a mean of 33 mo corrected age was assessed using the Bayley Scales of Infant Development, 3rd edition.
Adjusting for confounders, a 1% increase in postnatal docosahexaenoic acid (DHA) levels at early MRI was associated with 4.3-fold decreased odds of intraventricular hemorrhage, but was not associated with white matter injury or cerebellar haemorrhage. Higher DHA and lower linoleic acid (LA) levels at early MRI were associated with lower diffusivity in white matter tracts and corresponding improved developmental scores in follow-up.
Higher DHA and lower LA levels in the first few weeks of life are associated with decreased intraventricular haemorrhage, improved microstructural brain development, and improved outcomes in preterm born children. Early and possibly antenatal interventions in high-risk pregnancies need to be studied for potential benefits in preterm developmental outcomes.
Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with ...advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, 89Zr-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype.
The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.
Although virtue ethics has emerged as an influential ethical theory within the academy, universities have not generally taken up the practical task of virtue cultivation. Some academics even resist ...the effort altogether. In response, this article presents an early-stage evaluation of one effort to cultivate virtue in postgraduate students, a theoretically derived and empirically measured character development programme at the University of Oxford. The study uses a pre- and post-test experimental design to assess whether participation results in measurable growth of four character virtues. Quantitative data offer evidence for modest improvement with respect to two of the four focal virtues measured, while qualitative data suggest that future iterations should ensure that participants are given both reflective, conceptual tools and practical, everyday tasks to cultivate virtue. The article provides both empirical support and future directions for ongoing research and programme development for cultivating virtue in the university.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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