Faculty Bibliography

OBJECTIVES/OBJECTIVE:Most pediatric residency programs introduce PICU rotations in postgraduate year (PGY) 2, although it is unclear whether this timing best supports trainees' skill development. Introduction during PGY1 may pose challenges due to clinical intensity, but could also have benefits in uniquely preparing residents for PGY2 responsibilities and autonomy. To address this question, this study explored the experiences and self-perceived impacts of a PGY1 PICU rotation among senior pediatric residents. DESIGN/METHODS:A multi-institutional qualitative study was conducted using semi-structured interviews of senior (PGY2 and PGY3) residents who completed a PGY1 PICU rotation. Stratified purposive sampling was used at both institutional and resident levels. Data were coded using constant comparison and analyzed thematically. SETTING/METHODS:Seven institutions requiring a 4-week PGY1 PICU rotation. PARTICIPANTS/METHODS:Senior pediatric residents at participating institutions. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Twenty-one interviews across seven institutions identified three key themes: 1) PGY1s can succeed in the PICU setting when supervisors actively cultivate a learning environment of inclusion, support, and appropriate autonomy; 2) PGY1 PICU rotations can foster self-perceived competence in skills that translate to the PGY2 year; and 3) Participants generally believed the benefits of early PICU exposure outweighed the challenges. CONCLUSIONS:PGY1 PICU rotations can fall within the Zone of Proximal Development when the experience includes strong supervisory support. Findings highlighted the importance of psychologic safety for optimal learning, suggesting that strengthening psychologic safety may enhance the educational experience and outcomes. Further research exploring the impact of PGY1s on team dynamics and patient care, and comparing the effects of PGY1 vs. PGY2 introduction, could guide evidence-based recommendations on the optimal sequencing of PICU rotations for pediatric residents.

PURPOSE/OBJECTIVE:Hemorrhagic radiation cystitis (HRC), a complication of pelvic radiation therapy, results from hypoxic and ischemic injury and causes urinary symptoms like hematuria, dysuria, frequency, urgency, and retention. Hyperbaric Oxygen Therapy (HBOT), where patients breathe 100% oxygen at increased atmospheric pressure, enhances tissue oxygenation, promoting neovascularization and reducing inflammation. The optimal pressure remains unclear, though pressures above 1.41 ATA are efficacious, with higher pressures increasing side effect risks. This study compares the efficacy and side effects of 2.0 versus 2.5 ATA therapy at two sites. MATERIALS AND METHODS/METHODS:A retrospective chart review of 93 patients treated for HRC at two sites was conducted. Data on demographics, efficacy (symptom reduction), and side effects were analyzed using GraphPad Prism. Chi-squared and Mann-Whitney tests were used for statistical analysis. Mixed effects logistic regression models were used. RESULTS AND CONCLUSIONS/CONCLUSIONS:Fewer patients treated at 2.5 ATA experienced gross hematuria within 1-year post-therapy compared to those treated at 2.0 ATA (p < 0.05). However, time to hematuria recurrence showed no difference between the groups (10.2 vs. 9.6 months). No difference was observed in other urinary symptoms. Adverse events were increased at 2.5 ATA when analyzed with a mixed effects logistic regression model. Other treatment parameters, including treatment number and duration, were similar across groups. These findings suggest an association between 2.5 ATA treatment and lower rates of hematuria recurrence, but further randomized studies are necessary to determine causality. Future studies should also assess quality of life and explore variations in treatment protocol for efficacy and safety. CLINICAL TRIAL REGISTRATION/BACKGROUND:As this is a retrospective study, no clinical trial registration is necessary.

Drug-induced liver injury describes the result of toxicity to the liver from offending drugs and/or their metabolites. Most cases are acute and resolve quickly after the medication is discontinued. It is a diagnosis of exclusion after ruling out other causes of liver injury, such as infectious and autoimmune etiologies. When drug-induced liver injury is suspected, the culprit can be determined by establishing a temporal relationship between drug exposure and the development of signs and symptoms of liver injury. In this case presentation, we discuss a patient who developed liver injury from pyridostigmine in the management of acute colonic pseudo-obstruction (Ogilvie syndrome).

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only postmortem, but can present with an array of cognitive, behavioral, mood, and motor symptoms. However, traumatic brain injury is also associated with increased risk of Alzheimer's disease (AD) and may lead to comorbid neuropathology. Characterization of the in vivo biomarkers of CTE is a necessary next step to facilitate accurate diagnoses. We examined the profile of cerebrospinal fluid (CSF) biomarkers of amyloid-β, total tau (tTau), and phospho-tau (pTau) in a cohort of former professional (PRO, n = 100) and college (COL, n = 40) football players at high risk of CTE compared to asymptomatic unexposed controls (UE, n = 43). CSF was collected under controlled conditions using collection, processing, and cryostorage kits provided by the DIAGNOSE CTE Research Project Biomarker Core, and concentrations of Aβ₄₀, Aβ₄₂, tTau, and pTau (pTau₁₈₁, pTau₂₁₇, pTau₂₃₁) were measured at the University of Gothenburg, Sweden, using immunoassays. Associations between CSF biomarker levels with football history, and diagnosis of traumatic encephalopathy syndrome (TES) were examined using linear regression, and corrected for age, education, APOE-ε4 allele status, race, and body mass index. Our analysis revealed that football exposure affected both CSF Aβ₄₀ (p = 0.039) and Aβ₄₂ (p = 0.038), particularly among those under 60 years of age in the PRO compared to the UE exposure group. Among former football players, estimates of RHI exposure were not generally associated with CSF Aβ, tTau, and pTau biomarker levels. CSF Aβ₄₀ (p = 0.0041) and Aβ₄₂ (p = 0.011) were lower in former football players with TES diagnosis compared to unexposed participants, although CSF Aβ, tTau, and pTau biomarker levels did not differ between former players with and without a TES diagnosis. Among former football players, reduced CSF Aβ₄₀ (p = 0.011) and Aβ₄₂ (p = 6e-04) were observed in those with cognitive impairment compared to those with neurobehavioral dysregulation. The findings of significant associations of reduced CSF Aβ levels with RHI in elite football players are in line with recent postmortem studies; however, the lack of relationship with CSF tTau and pTau species observed to be altered in the setting of AD suggests that the pathological features of CTE reflected in fluid biomarkers are complex and require further study. The overlapping comorbid age-dependent features of neurodegeneration that occur in those at risk for CTE suggest that tau pathology in CTE is not reliably reflected by currently available fluid biomarkers and that the use of multiple biomarkers related to the compound characteristics of CTE may be required for early detection.

The prevalence and incidence of prediabetes in children and youth continue to increase in parallel with the obesity epidemic. While prediabetes is defined by elevated HbA1c and/or impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), the risk of clinical disease is a continuum. Individuals with prediabetes are at a higher risk of developing youth-onset type 2 diabetes, which is considered a more aggressive form of the disease. This condition is associated with increased cardiovascular and metabolic risks and leads to an earlier onset of complications compared to adults with type 2 diabetes. Additionally, significant damage to beta cells may occur even before dysglycemia develops. Recent data indicate that mortality rates are higher in youths with type 2 diabetes compared to those with type 1 diabetes. Childhood prediabetes and cardiovascular complications associated with it are a significant health concern. This review provides the latest insights into this complex issue. We will present an overview of pathophysiology, screening methods, and therapeutic options to prevent the progression from prediabetes to type 2 diabetes in children. In summary, it is crucial to identify prediabetes in children, as this underscores the importance of appropriate screening and timely intervention.

Increased fasting and postprandial triglyceride levels are risk factors for cardiovascular disease (CVD). Partially metabolized triglyceride-rich lipoproteins (TRLs) termed remnants are created when intestinally-derived chylomicrons and liver secreted very low density lipoproteins (VLDLs) interact with lipoprotein lipase (LpL) situated on the luminal surface of capillary endothelial cells. Higher circulating remnant levels have been implicated as the reason for the relationship between TRL levels and CVD. We hypothesized that nascent lipoproteins not only remnants are atherogenic. To test this, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl^-/-) and LDLR knockdown (Ldlr^kd) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl^-/-/Ldlr^kd mice than control Ldlrkd mice. Aorta from hypertriglyceridemic mice had changes in the transcriptomes of endothelial cells, macrophages, and smooth muscle cells indicating vascular inflammation. Our data show that intact TRLs contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease and prove that non-remnant TRLs are not benign.

BACKGROUND:While immune checkpoint inhibitors (ICI) induce potent responses against several systemic malignancies, clinical efficacy against high-grade glioma has been limited by immunosuppression, low mutational burden and limited lymphocyte infiltration into tumors. Laser interstitial thermal therapy (LITT) induces coagulative necrosis and disrupts the peritumoral blood-brain barrier (BBB), creating a potentially antigenic milieu. We hypothesized that neoadjuvant and adjuvant ICI would synergize with LITT to potentiate antitumor immune responses and enhance survival. METHODS:This retrospective study is an exploratory case series that includes 9 adult patients with recurrent IDH wild-type glioblastoma (GBM, n = 6), IDH mutant high-grade astrocytoma (n = 2) and H3K27M mutant diffuse midline glioma (n = 1). All patients received neoadjuvant anti-PD1 ICI prior to LITT and most received adjuvant ICI (8/9). Disease burden was followed through radiographic volume segmentation of gadolinium-enhancing disease. Patients were followed for progression-free (PFS) and overall survival (OS). RESULTS:). There were no perioperative complications. All patients showed an initial increase in gadolinium-enhancing volume after LITT. Seven of 9 (78 %) patients demonstrated subsequent regression in total gadolinium-enhancing volume. Three non-contiguous satellite lesions naïve to laser ablation exhibited complete or near-complete regression in 2 patients. Median PFS was 5.90 months (range 1.00-41.23), and median OS was 9.97 months (range 1.20-41.23). CONCLUSIONS:Combination therapy with neoadjuvant and adjuvant pembrolizumab and LITT is feasible and safe in recurrent high-grade glioma. Responses may be more robust in certain molecular subtypes of glioma. Further studies are needed to investigate this potential synergy.