Beyond the bias! Sex distribution in paediatric growth hormone deficiency reexamined.

OBJECTIVES: Various biases pertaining to stature account for a male sex predominance in growth hormone deficiency (GHD) cases diagnosed by endocrinology clinics. This manuscript will assess the sex distribution when biases are minimised. METHODS: Retrospective chart review was conducted on patients diagnosed with GHD between 3 and 16 years of age. The sex distribution of cases was ascertained according to: (1) peak GH (pGH) by groups; based on growth hormone provocative testing, (2) pituitary gland imaging results, and (3) isolated GHD (IGHD) versus multiple pituitary hormone deficiencies (MPHD). The relative frequency of each sex was compared according to these subgroups with significance evaluated at α = .05 level. RESULTS: Of the 5880 clinic referrals for short stature, there were 3709 boys (63%) and 2171 girls (37%). Of these, 20% of boys (n = 745) and 15.3% of girls (n = 332) underwent provocative testing for GHD. Of those tested, 39.2% of boys (n = 292) and 32.2% of girls (n = 107) were diagnosed with GHD, all p < .001. There was a male predominance in GHD cases based on pGH or GHD severity. Though not significant, girls were more likely than boys to have MPHD (p = .056), even across pGH groups (p = .06). Both boys and girls had a similar distribution of imaging abnormalities. CONCLUSION: Stratifying by sex, we found similar percentages of pituitary imaging abnormalities (including tumours) and the number of pituitary hormone deficiencies in boys and girls as the cause of GHD. For these classifications, we did not find the historically reported male sex predominance.

Urinary biomarkers associated with acute kidney injury in pediatric mechanical circulatory support patients.

BACKGROUND: In patients requiring mechanical circulatory support (MCS), the incidence of acute kidney injury (AKI) is between 37 and 63%. In this study, we performed an exploratory analysis evaluating the relationship of multiple urine biomarkers with AKI development in pediatric MCS patients. METHODS: This is a single center retrospective study in a pediatric cohort receiving MCS from August 2014 to November 2020. We measured 14 urine biomarkers of kidney injury on day 1 following MCS initiation and analyzed their association with development of AKI in the first 7 days of MCS initiation. RESULTS: Sixty patients met inclusion criteria. Patients with AKI were more likely to be supported by venoarterial extracorporeal membrane oxygenation (65% vs. 8.3%, p < 0.001), compared to the no AKI group and less likely to have ventricular assist devices (10% vs. 50%, p < 0.001). There was a significant increase in the median urine albumin and urine osteoactivin in the AKI group, compared to the no AKI group (p = 0.020 and p = 0.018, respectively). When normalized to urine creatinine (UCr), an increased log osteoactivin/UCr was associated with higher odds of AKI development (OR: 2.05; 95% CI: 1.07, 4.44; p = 0.028), and higher log epidermal growth factor (EGF)/UCr (OR: 0.41; 95% CI: 0.15, 0.96) was associated with decreased odds of AKI. CONCLUSIONS: Early increase in urine osteoactivin is associated with AKI development within 7 days of MCS initiation in pediatric patients. Contrary, an increased urine EGF is associated with kidney protection. A higher resolution version of the Graphical abstract is available as Supplementary information.

Positive fluid balance and diuretic therapy are associated with mechanical ventilation and mortality in preterm neonates in the first fourteen postnatal days.

BACKGROUND: Fluid overload leads to poor neonatal outcomes. Diuretics may lower the rates of mechanical ventilation (MV) and mortality in neonates with fluid overload. METHODS: This is a retrospective study of preterm neonates ≤ 36 weeks of gestational age (GA) in the first 14 postnatal days in a level IV NICU in 2014-2020. We evaluated the epidemiology of fluid balance in the first 14 postnatal days and its association with MV and mortality and studied the association of diuretics with fluid balance, MV, and mortality. RESULTS: In 1383 included neonates, the overall median lowest and peak fluid balances were - 7.8% (IQR: - 11.7, - 4.6) and 8% (3, 16) on days 3 (2, 5) and 13 (5, 14), respectively. Fluid balance distribution varied significantly by GA. Peak fluid balance of ≥ 10% was associated with increased odds of MV on days 7 and 14 with highest odds ratios (OR) of MV in neonates with fluid balance ≥ 15%. Peak fluid balance of ≥ 15% was associated with the greatest odds of mortality. Diuretics were used more frequently in neonates with younger GA, smaller birthweight, positive fluid balance, and those on MV. CONCLUSIONS: Positive fluid balance negatively impacts pulmonary status. The odds of MV and death increase significantly as peak fluid balance percentage increases in all GA groups. The impact of diuretics on MV and death in preterm neonates needs further evaluation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Accelerated hypofractionated radiation for elderly or frail patients with a newly diagnosed glioblastoma: A pooled analysis of patient-level data from 4 prospective trials.

BACKGROUND: The standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) is safe and efficacious. METHODS: Elderly or frail patients with GBM treated with 52.5 Gy in 15 fractions were pooled from 3 phase 1/2 studies and a prospective observational study. Overall survival (OS) and progression-free survival (PFS) were defined time elapsing between surgery/biopsy and death from any cause or progression of disease. RESULTS: Sixty-two newly diagnosed patients were eligible for this pooled analysis of individual patient data. The majority (66%) had a Karnofsky performance status (KPS) score <70. The median age was 73 years. The median OS and PFS were 10.3 and 6.9 months, respectively. Patients with KPS scores ≥70 and <70 had a median OS of 15.3 and 9.5 months, respectively. Concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). There was no grade 4/5 toxicity. CONCLUSIONS: This is the only analysis of elderly/frail patients with GBM prospectively treated with a hypofractionated radiation regimen that is isoeffective to the Stupp regimen. Treatment was well tolerated and demonstrated excellent OS and PFS compared with historical studies. This regimen gives the elderly/frail population an alternative to regimens with a lower BED. Randomized trials are needed to validate these results.

Patient-parent perceptions of transition readiness in Turner syndrome and associated factors.

OBJECTIVE: Medical care transition to adult care presents challenges for individuals with complex medical conditions such as Turner syndrome (TS). The goals of this study were to: (1) identify factors associated with transition readiness; (2) examine associations and differences between patients' and parents' perceptions of readiness using Transition Readiness Assessment Questionnaire (TRAQ). METHODS: In a prospective cross-sectional study, girls with TS 12-25 years and one parent were recruited from 11/2019 to 12/2020. Three questionnaires were administered (demographic/clinical questionnaire, TRAQ, and TS Transition Readiness Assessment Questionnaire [TS-TRAQ]). Medical records were reviewed for karyotype and personal medical history. Descriptive statistics, Spearman's correlation, paired sample t tests, and linear regression were used to examine readiness and associated factors. RESULTS: Of 44 eligible patients, 35 patients and 30 parents completed the study. Patient age, education, and life skills were associated with a higher TRAQ score (p < .001). Greater TS knowledge was associated with higher readiness (p < .05). Readiness score for patient and parental perception of patient's readiness were correlated (r = .83; p < .01). Within patient-parent dyads, patients had higher readiness (p < .01). TRAQ and TS-TRAQ scores were correlated (r = .69; p < .01). CONCLUSIONS: Increasing patient age, patient education, life skills, confidence, and higher social/emotional scores were associated with a higher total TRAQ. Patient and parent perceived readiness were correlated and scores within dyads were different. Patients had higher perceived readiness. Positive correlations between TRAQ and TS-TRAQ suggest this tool may be a useful resource. Given the unique neurocognitive profile and social/emotional challenges among girls with TS, future research should include both patients and parents, and focus on validating TS-specific transition readiness tools.

Update of a prognostic survival model in head and neck squamous cell carcinoma patients treated with immune checkpoint inhibitors using an expansion cohort.

BACKGROUND: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. METHODS: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. RESULTS: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. CONCLUSIONS: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.

Magnetic Resonance Elastography of Intervertebral Discs: Spin-Echo Echo-Planar Imaging Sequence Validation.

BACKGROUND: Magnetic resonance elastography (MRE) is an imaging technique that can noninvasively assess the shear properties of the intervertebral disc (IVD). Unlike the standard gradient recalled echo (GRE) MRE technique, a spin-echo echo-planar imaging (SE-EPI) sequence has the potential to improve imaging efficiency and patient compliance. PURPOSE: To validate the use of an SE-EPI sequence for MRE of the IVD compared against the standard GRE sequence. STUDY TYPE: Cross-over. SUBJECTS: Twenty-eight healthy volunteers (15 males and 13 females, age range: 19-55). FIELD STRENGTH/SEQUENCE: 3 T; GRE, SE-EPI with breath holds (SE-EPI-BH) and SE-EPI with free breathing (SE-EPI-FB) MRE sequences. ASSESSMENT: MRE-derived shear stiffnesses were calculated via principal frequency analysis. SE-EPI derived shear stiffness and octahedral shear strain signal-to-noise ratios (OSS-SNR) were compared against those derived using the GRE sequence. The reproducibility and repeatability of SE-EPI stiffness measurements were determined. Shear stiffness was evaluated in the nucleus pulposus (NP) and annulus fibrosus (AF) regions of the disc. Scan times between sequences were compared. STATISTICAL TESTS: Linear mixed models, Bland-Altman plots, and Lin's concordance correlation coefficients (CCCs) were used with P < 0.05 considered statistically significant. RESULTS: Good correlation was observed between shear stiffnesses derived from the SE-EPI sequences with those derived from the GRE sequence with CCC values greater than 0.73 and 0.78 for the NP and AF regions, respectively. OSS-SNR was not significantly different between GRE and SE-EPI sequences (P > 0.05). SE-EPI sequences generated highly reproducible and repeatable stiffness measurements with CCC values greater than 0.97 in the NP and AF regions and reduced scan time by at least 51% compared to GRE. SE-EPI-BH and SE-EPI-FB stiffness measurements were similar with CCC values greater than 0.98 for both regions. DATA CONCLUSION: SE-EPI-based MRE-derived stiffnesses were highly reproducible and repeatable and correlated with current standard GRE MRE-derived stiffness estimates while reducing scan times. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Fractionated pre-operative stereotactic radiotherapy for patients with brain metastases: a multi-institutional analysis.

BACKGROUND: The current standard of care for patients with a large brain metastasis and limited intracranial disease burden is surgical resection and post-operative single fraction stereotactic radiosurgery (SRS). However, post-operative SRS can still lead to substantial rates of local failure (LF), radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated treatments may improve local control by allowing delivery of higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) can minimize rates of LF, RN, and MD. METHODS: A retrospective, multi-institutional analysis was conducted and included patients who had pre-operative FSRT for a large or symptomatic brain metastasis. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. A primary measurement was the rate of a composite endpoint of (1) LF, (2) MD, and/or (3) Grade 2 or higher (symptomatic) RN. RESULTS: 53 patients with 55 lesions were eligible for analysis. FSRT was prescribed to a dose of 24-25 Gy in 3-5 fractions. There were 0 LFs, 3 Grade 2-3 RN events, and 1 MD occurrence, which corresponded to an 8% per-patient composite endpoint event rate. CONCLUSIONS: In this study, the composite endpoint of 8% for pre-operative FSRT was improved compared to previously reported rates with post-operative SRS of 49-60% (N107C, Mahajan etal. JCOG0504) and pre-operative SRS endpoints of 20.6% (PROPS-BM). Pre-operative FSRT appears to be safe, effective, and may decrease the incidence of adverse outcomes. Prospective validation is needed.

Dose-escalated accelerated hypofractionation for elderly or frail patients with a newly diagnosed glioblastoma.

BACKGROUND: The standard of care for elderly glioblastoma patients is 40 Gy in 15 fraction radiotherapy with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions. METHODS: Elderly patients (≥ 65 years old) who received hypofractionated radiation with TMZ from 2010 to 2020 were included in this analysis. Overall survival (OS) and progression free survival were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared between patients who received 40 and 52.5 Gy. Univariable and multivariable analyses were performed. RESULTS: Sixty-six newly diagnosed patients were eligible for analysis. Thirty-nine patients were treated with 40 Gy in 15 fractions while twenty-seven were treated with 52.5 Gy in 15 fractions. Patients had no significant differences in age, sex, methylation status, or performance status. OS was superior in the 52.5 Gy group (14.1 months) when compared to the 40 Gy group (7.9 months, p = 0.011). Isoeffective dosing to 52.5 Gy was shown to be an independent prognostic factor for improved OS on multivariable analysis. CONCLUSIONS: Isoeffective dosing to 52.5 Gy in 15 fractions was associated with superior OS compared to standard of care 40 Gy in 15 fractions. These hypothesis generating data support accelerated hypofractionation in future prospective trials.

Caspase-11 counteracts mitochondrial ROS-mediated clearance of Staphylococcus aureus in macrophages.

Methicillin-resistant Staphylococcus aureus (MRSA) is a growing health concern due to increasing resistance to antibiotics. As a facultative intracellular pathogen, MRSA is capable of persisting within professional phagocytes including macrophages. Here, we identify a role for CASP11 in facilitating MRSA survival within murine macrophages. We show that MRSA actively prevents the recruitment of mitochondria to the vicinity of the vacuoles they reside in to avoid intracellular demise. This process requires CASP11 since its deficiency allows increased association of MRSA-containing vacuoles with mitochondria. The induction of mitochondrial superoxide by antimycin A (Ant A) improves MRSA eradication in casp11-/- cells, where mitochondria remain in the vicinity of the bacterium. In WT macrophages, Ant A does not affect MRSA persistence. When mitochondrial dissociation is prevented by the actin depolymerizing agent cytochalasin D, Ant A effectively reduces MRSA numbers. Moreover, the absence of CASP11 leads to reduced cleavage of CASP1, IL-1ß, and CASP7, as well as to reduced production of CXCL1/KC. Our study provides a new role for CASP11 in promoting the persistence of Gram-positive bacteria.

Challenges of diagnosing pediatric hypertension using ambulatory blood pressure monitoring.

BACKGROUND: Ambulatory blood pressure monitoring (ABPM) measures mean arterial pressure (MAP) then extrapolates systolic and diastolic blood pressure (BP) values. Pediatric guidelines recommend using calculated systolic and diastolic BP rather than measured MAP for diagnosis of ambulatory hypertension (HTN). The 95th percentile BP that defines ambulatory HTN is higher in some children than thresholds used to define ambulatory HTN in adults. METHODS: This is a retrospective study of patients who underwent 24-h ABPM. The level of agreement in ambulatory HTN diagnosis using MAP vs. systolic/diastolic BP was evaluated using Cohen's kappa coefficient. Similar analysis was done to assess agreement in HTN diagnosis using adult vs. pediatric criteria for males taller than 165 cm. RESULTS: A total of 263 ABPM studies were included. There was good agreement for diagnosis of HTN using MAP or systolic/diastolic BP (k = 0.75; 95% CI: 0.67-0.83). However, there was disagreement between the methods in 12% (n = 31) of subjects. Similarly, there was good agreement (k = 0.70; 95% CI: 0.56-0.85) between pediatric and adult criteria for HTN diagnosis. Nineteen patients were found to be hypertensive (9 using MAP criteria, 10 using adult criteria) who would not have met ambulatory HTN criteria using current pediatric guidelines. CONCLUSIONS: Inclusion of MAP along with systolic and diastolic BP in ABPM analysis alongside using adult criteria for diagnosing HTN in male children ≥ 165 cm may improve accuracy of pediatric HTN diagnosis and reduce false negative rate. Larger studies are needed to assess the clinical validity of these results. Graphical abstract.

Diuretic therapy and acute kidney injury in preterm neonates and infants.

BACKGROUND: Acute kidney injury (AKI) in preterm infants is associated with prolonged hospitalization and high mortality. Diuretic therapy has been used to enhance urine output in preterm infants with AKI. Treatment with diuretics, prescription patterns, and relationship with length of stay (LOS), mechanical ventilation (MV), and mortality in preterm infants who also had AKI have not been fully evaluated. METHODS: This multicenter retrospective study used the Pediatric Hospital Information System database. We included 2121 preterm infants with AKI diagnosis from 46 hospital Neonatal Intensive Care Units (NICUs) born <37 weeks gestational age (GA). Treatment with diuretics, practice patterns across 46 NICUs in the USA, and associated outcomes including LOS, MV, and mortality were evaluated. RESULTS: Seventy-six percent of infants received at least one dose of diuretics (median treatment 18 days). Diuretic prescription varied significantly across hospitals and ranged from 42 to 96%. Diuretics were used more frequently in infants with younger GA and smaller birth weight. Infants with older GA who received diuretics at or before 28 days postnatally had worse survival even after adjusting for known confounders. CONCLUSIONS: Preterm infants with AKI diagnosis were frequently treated with diuretics. Moreover, infants with younger GA and smaller birth weight were more likely to receive diuretics. Worse survival in infants with older GA who received diuretics could be the result of more underlying severe illness in these infants and not the cause of more severe illness. Prospective studies are needed to best determine patient safety and outcomes with diuretic treatment in preterm infants with AKI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Exploring genetic counselors' perceptions of usefulness and intentions to use refined risk models in clinical care based on the Technology Acceptance Model (TAM).

Pathogenic germline mutations in the BRCA1 or BRCA2 genes are associated with an elevated lifetime risk for breast (50%-85% risk) and ovarian cancer (20%-40% risk). Genome-wide association studies have identified over 100 genetic variants associated with modified breast and/or ovarian cancer risk in BRCA1 and BRCA2 carriers. Risk models generated based on these variants have shown that these genetic modifiers strongly influence absolute risk of developing breast or ovarian cancer in BRCA mutation carriers. There is a lack of understanding, however, about the clinical applicability and utility of these risk models. To investigate this gap, we collected survey data from 274 cancer genetic counselors (GCs) through the National Society of Genetic Counselors Cancer Special Interest Group. Questions assessed perceptions of usefulness and intentions of genetic counselors to use these refined risk models in clinical care based on the Technology Acceptance Model (TAM). We found that GCs' reactions to the estimates were largely positive, though they thought the possibility of changing management based on results was unlikely. Additionally, we found that more experienced GCs were more likely to consider refined risk estimates in clinic. Support also was provided for core predictions within the TAM, whereby the perceived usefulness (indirect effect est. = 0.08, 95% CI: [0.04, 0.13]) and perceived ease of use (indirect effect est. = 0.078, 95% CI: [0.04, 0.13]) of refined risk estimates were indirectly associated with intentions to use via attitudes.

The First 100 Seconds of Sleep of rEEGs Can Be a Reliable Scoring Method for D/EE-SWAS.

PURPOSE: Developmental/epileptic encephalopathy with spike wave activation with sleep, formerly known as electrical status epilepticus in sleep, is an electrographic pattern in which the interictal epileptiform activity is augmented by transition to sleep. Recent studies demonstrate the utility of the first 100 seconds of sleep of long-term monitoring (LTM) as a scoring method for electrical status epilepticus in sleep. Our aim was to measure the reliability of the spike-wave index (SWI) of the first 100 seconds of sleep of routine EEG (rEEG) as a tool for diagnosis of developmental/epileptic encephalopathy with spike wave activation with sleep. METHODS: Approximately three hundred forty LTMs were reviewed, and 25 studies from 25 unique patients had comparable rEEGs. Two neurophysiologists calculated the SWI of the first 100 seconds of spontaneous stage II non-random eye movement sleep, the first 5-minute bin of sleep, and three separate 5-minute bins throughout sleep in LTM. This was compared to the SWI of the first 100 seconds of sleep in rEEG. Agreement was analyzed using Lin's concordance correlation coefficient (CCC). RESULTS: Using 50% as a diagnostic cut-off, we observed moderate agreement between the SWI of the first 100 seconds of sleep of rEEG and three bin LTM (CCC = 0.94, 95% CI: 0.88-0.97). Agreement was slightly higher for the comparison to first bin LTM SWI (CCC = 0.96, 95% CI: 0.92-0.98) and first 100 seconds LTM SWI (CCC = 0.96, 95% CI: 0.92-0.98). CONCLUSIONS: This study demonstrates the first 100 seconds of sleep of rEEG technique as a time efficient diagnostic tool for patients with concern for developmental/epileptic encephalopathy with spike wave activation with sleep.

Nucleus pulposus structure and function assessed in shear using magnetic resonance elastography, quantitative MRI, and rheometry.

Background: In vivo quantification of the structure-function relationship of the intervertebral disc (IVD) via quantitative MRI has the potential to aid objective stratification of disease and evaluation of restorative therapies. Magnetic resonance elastography (MRE) is an imaging technique that assesses tissue shear properties and combined with quantitative MRI metrics reflective of composition can inform structure-function of the IVD. The objectives of this study were to (1) compare MRE- and rheometry-derived shear modulus in agarose gels and nucleus pulposus (NP) tissue and (2) correlate MRE and rheological measures of NP tissue with composition and quantitative MRI. Method: MRE and MRI assessment (i.e., T1ρ and T2 mapping) of agarose samples (2%, 3%, and 4% (w/v); n = 3-4/%) and of bovine caudal IVDs after equilibrium dialysis in 5% or 25% PEG (n = 13/PEG%) was conducted. Subsequently, agarose and NP tissue underwent torsional mechanical testing consisting of a frequency sweep from 1 to 100 Hz at a rotational strain of 0.05%. NP tissue was additionally evaluated under creep and stress relaxation conditions. Linear mixed-effects models and univariate regression analyses evaluated the effects of testing method, %agarose or %PEG, and frequency, as well as correlations between parameters. Results: MRE- and rheometry-derived shear moduli were greater at 100 Hz than at 80 Hz in all agarose and NP tissue samples. Additionally, all samples with lower water content had higher complex shear moduli. There was a significant correlation between MRE- and rheometry-derived modulus values for homogenous agarose samples. T1ρ and T2 relaxation times for agarose and tissue were negatively correlated with complex shear modulus derived from both techniques. For NP tissue, shear modulus was positively correlated with GAG/wet-weight and negatively correlated with %water content. Conclusion: This work demonstrates that MRE can assess hydration-induced changes in IVD shear properties and further highlights the structure-function relationship between composition and shear mechanical behaviors of NP tissue.

Concentration of novel urinary tract infection biomarkers in neonates.

Urinary tract infections (UTIs) are a common comorbidity in hospitalized neonates. The current UTI diagnostics have several limitations including invasive collection of urinary samples to ensure sterility, risk of contamination and lack of consensus definitions of UTI based on urine culture. Antimicrobial peptides (AMPs) have been recently utilized as novel biomarkers that can efficiently and accurately diagnose pediatric UTI. However, the concentration of AMPs in neonatal urine is not well-defined. Urine from neonates admitted to a single level IV neonatal intensive care unit was obtained to determine baseline concentration of two AMPs, Ribonuclease 7 (RNase 7) and Beta Defensin-1 (BD-1) and to define the relationship between AMP concentration and gestational age (GA). AMP levels were normalized to urine creatinine. RNase 7 and BD-1 were expressed in neonatal urine (n = 66) regardless of GA and as early as 22 weeks gestation. Urinary concentrations of both AMPs decreased as GA and birthweight increased. The overall median urinary RNase 7/UCr and BD-1/UCr values were 271 ng/mg, and 116 ng/mg, respectively. Median urinary concentrations of RNase 7/UCr for infants born at < 27, 27-32, 33-35 and ≥ 36 weeks were 569, 308, 254, and 124 ng/mg respectively. Similarly, the concentrations of BD-1/UCr at these GA were 166, 115, 108, and 14 ng/mg, respectively. Baseline neonatal urinary concentration of two AMPs (RNase 7 and BD-1) and the variation by GA were identified. This is an essential first step toward the potential utilization of AMPs in improving neonatal UTI diagnostics.

Audiological Outcomes of Weekly vs. Triweekly Cisplatin in Head and Neck Cancer with Cochlear-Sparing Intensity-Modulated Radiation Therapy.

Cisplatin, one of the most ototoxic anti-neoplastic agents, causes permanent hearing loss in up to 90% of patients. We assessed ototoxicity rates and prospectively collected audiologic outcomes of patients receiving low-dose or high-dose cisplatin with concurrent cochlear-sparing intensity-modulated radiation therapy (IMRT). Patients with head and neck squamous cell carcinoma (HNSCC) receiving definitive or adjuvant cisplatin-based chemoradiotherapy (CRT) were analyzed. Cisplatin was administered either in low doses weekly (40 mg/m2) for up to seven doses or in high doses triweekly (100 mg/m2) for up to three doses. Cochlear-sparing IMRT was delivered in all cases. Audiologic data were prospectively collected before, during, and after treatment completion. The primary endpoint was a hearing change grade of ≥3 after CRT completion. Of the 96 HNSCC patients evaluated, 69 received weekly cisplatin and 58 received definitive CRT. Of patients receiving weekly cisplatin, 13% developed ≥G3 ototoxicity vs. 56% of patients who received triweekly cisplatin (p < 0.001). In multivariable modeling, the cisplatin dose schedule remained significant (OR: 8.4, 95%CI: 2.8-27.8, p < 0.001) for risk of severe irreversible ototoxicity. Triweekly cisplatin CRT significantly increased the ≥G3 severe irreversible ototoxicity risk compared to low-dose weekly cisplatin, irrespective of the cumulative cisplatin dose, even with the use of cochlear-sparing IMRT. No significant difference in oncologic outcomes was observed between the two schedules.

Characterization and modulation of the pro-inflammatory effects of immune cells in the canine intervertebral disk.

Background: Intervertebral disk (IVD) degeneration affects both humans and canines and is a major cause of low back pain (LBP). Mast cell (MC) and macrophage (MØ) infiltration has been identified in the pathogenesis of IVD degeneration (IVDD) in the human and rodent model but remains understudied in the canine. MC degranulation in the IVD leads to a pro-inflammatory cascade and activates protease activated receptor 2 (PAR2) on IVD cells. The objectives of the present study are to: (1) highlight the pathophysiological changes observed in the degenerate canine IVD, (2) further characterize the inflammatory effect of MCs co-cultured with canine nucleus pulposus (NP) cells, (3) evaluate the effect of construct stiffness on NP and MCs, and (4) identify potential therapeutics to mitigate pathologic changes in the IVD microenvironment. Methods: Canine IVD tissue was isolated from healthy autopsy research dogs (beagle) and pet dogs undergoing laminectomy for IVD herniation. Morphology, protein content, and inflammatory markers were assessed. NP cells isolated from healthy autopsy (Mongrel hounds) tissue were co-cultured with canine MCs within agarose constructs and treated with cromolyn sodium (CS) and PAR2 antagonist (PAR2A). Gene expression, sulfated glycosaminoglycan content, and stiffness of constructs were assessed. Results: CD 31+ blood vessels, mast cell tryptase, and macrophage CD 163+ were increased in the degenerate surgical canine tissue compared to healthy autopsy. Pro-inflammatory genes were upregulated when canine NP cells were co-cultured with MCs and the stiffer microenvironment enhanced these effects. Treatment with CS and PAR2 inhibitors mediated key pro-inflammatory markers in canine NP cells. Conclusion: There is increased MC, MØs, and vascular ingrowth in the degenerate canine IVD tissue, similar to observations in the clinical population with IVDD and LBP. MCs co-cultured with canine NP cells drive inflammation, and CS and PAR2A are potential therapeutics that may mitigate the pathophysiology of IVDD in vitro.

Comparing Outcomes Between Direct and ED Admissions for Neonatal Hyperbilirubinemia.

OBJECTIVES: Pediatric direct admissions (DA) have multiple benefits including reduced emergency department (ED) volumes, greater patient and provider satisfaction, and decreased costs without compromising patient safety. We sought to compare resource utilization and outcomes between patients with a primary diagnosis of neonatal hyperbilirubinemia directly admitted with those admitted from the ED. METHODS: Single-center, retrospective study at a large, academic, free-standing children's hospital (2017-2021). Patients were between 24 hours and 14 days old with a gestational age of ≥35 weeks, admitted with a primary diagnosis of neonatal hyperbilirubinemia. Outcomes included length of stay (LOS), time to clinical care, resource utilization, NICU transfer, and 7-day readmission for phototherapy. RESULTS: A total of 1098 patients were included, with 276 (25.1%) ED admissions and 822 (74.9%) DAs. DAs experienced a shorter median time to bilirubin level collection (1.9 vs 2.1 hours, P = .003), received less intravenous fluids (8.9% vs 51.4%, P < .001), had less bilirubin levels collected (median of 3.0 vs 4.0, P < .001), received phototherapy sooner (median of 0.8 vs 4.2 hours, P < .001), and had a shorter LOS (median of 21 vs 23 hours, P = .002). One patient who was directly admitted required transfer to the NICU. No differences were observed in the 7-day readmission rates for phototherapy. CONCLUSIONS: Directly admitting patients for the management of neonatal hyperbilirubinemia is a preferred alternative to ED admission as our study demonstrated that DAs had a shorter time to clinical care, shorter LOS, and less unnecessary resource utilization with no difference in 7-day readmissions for phototherapy.

Disease Control and Toxicity Outcomes after Stereotactic Ablative Radiation Therapy for Recurrent and/or Metastatic Cancers in Young-Adult and Pediatric Patients.

BACKGROUND: Pediatric patients with metastatic and/or recurrent solid tumors have poor survival outcomes despite standard-of-care systemic therapy. Stereotactic ablative radiation therapy (SABR) may improve tumor control. We report the outcomes with the use of SABR in our pediatric solid tumor population. METHODS: This was a single-institutional study in patients < 30 years treated with SABR. The primary endpoint was local control (LC), while the secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. The survival analysis was performed using Kaplan-Meier estimates in R v4.2.3. RESULTS: In total, 48 patients receiving 135 SABR courses were included. The median age was 15.6 years (interquartile range, IQR 14-23 y) and the median follow-up was 18.1 months (IQR: 7.7-29.1). The median SABR dose was 30 Gy (IQR 25-35 Gy). The most common primary histologies were Ewing sarcoma (25%), rhabdomyosarcoma (17%), osteosarcoma (13%), and central nervous system (CNS) gliomas (13%). Furthermore, 57% of patients had oligometastatic disease (≤5 lesions) at the time of SABR. The one-year LC, PFS, and OS rates were 94%, 22%, and 70%, respectively. No grade 4 or higher toxicities were observed, while the rates of any grade 1, 2, and 3 toxicities were 11.8%, 3.7%, and 4.4%, respectively. Patients with oligometastatic disease, lung, or brain metastases and those who underwent surgery for a metastatic site had a significantly longer PFS. LC at 1-year was significantly higher for patients with a sarcoma histology (95.7% vs. 86.5%, p = 0.01) and for those who received a biological equivalent dose (BED10) > 48 Gy (100% vs. 91.2%, p = 0.001). CONCLUSIONS: SABR is well tolerated in pediatric patients with 1-year local failure and OS rates of <10% and 70%, respectively. Future studies evaluating SABR in combination with systemic therapy are needed to address progression outside of the irradiated field.