Glucocorticoid-induced adrenal insufficiency and glucocorticoid withdrawal syndrome: Two sides of the same coin.

Diseases of the adrenal glands can lead to primary adrenal insufficiency, and suppression of the hypothalamic-pituitary-adrenal axis can cause secondary adrenal insufficiency (adrenal suppression). The most common cause of adrenal suppression is exogenous steroids, a condition recently termed glucocorticoid-induced adrenal insufficiency (GIAI). Similarly, weaning from high doses of glucocorticoids or giving insufficient glucocorticoid replacement after curative surgery for endogenous hypercortisolism (Cushing syndrome) can lead to glucocorticoid withdrawal syndrome, which overlaps with GIAI.

[Clinical features and lymphocyte subtypes in patients with IgG4-related diseases].

Objective: To deepen understanding of IgG4-related diseases (RDs), we analyzed the associated lymphocyte subtypes, and explored the pathogenesis and potential immunotherapeutic targets. Methods: Eighty-six patients with IgG4-RDs were enrolled, and their clinical characteristics, peripheral lymphocyte subtypes, and disease course were analyzed. Results: The mean age of the participants was 36-87(62±11) years; 51 were male (59.3%) and 35 were women (40.7%); and 34.9% had a history of allergy. Follow-up lasted 4.8 (0.4, 14.1) months. The most common symptoms were abdominal pain, and submandibular gland and lacrimal gland swelling (each 20.9%). Sixty-five (75.6%) participants had multiple organ involvement, and the most frequently affected organs were the pancreas (52.3%), submandibular gland (51.2%), and lacrimal gland (34.9%). A high eosinophil count; high IgE, IgG, IgG1, and IgG4 concentrations; and low complement C3 and C4 concentrations were present in 18.8% (16/85), 30.0% (24/80), 72.9% (62/85), 58.3% (28/48), 89.5% (77/86), 61.2% (52/85), and 50.0% (42/84), respectively, of the participants. In addition, 64.7% (55/85) were positive for autoantibodies, and the most frequent was anti-nuclear antibody (63.5%). The proportion of CD4+T lymphocytes increased in 25.7% (9/35) of the participants, which was accompanied by an increase in the ratio of CD4+/CD8+T lymphocytes (22.9%, 8/35). Importantly, most participants (90.0%, 18/20) had a high proportion of regulatory T (Treg) cells. High interleukin (IL)-2, IL-6, and IL-10 concentrations were present in 50.0% (11/22), 33.3% (10/30), and 16.7% (5/30), respectively, of the participants. Substantial lymphoplasmacytic infiltration, fibrosis, IgG4-positive plasma cell infiltration, and lymphoid follicle hyperplasia or ectopic formation were present in 79.2% (42/53), 67.9%(36/53), 35.8%(19/53) and 30.2% (16/53), respectively, of the participants. Fifty-three participants with detailed pathologic data were also further evaluated, of whom 24.5% (13/53), 3.8% (2/53), and 67.9% (36/53) had definite, probable, and possible diagnoses; and 3.8% (2/53) could not be diagnosed. Compared with baseline, the percentage of eosinophils and the IgE, IgG, and IgG4 concentrations decreased significantly; and the complement C3 and C4 concentrations had increased significantly after 6 months of treatment (all P<0.05). The IgG4 concentration after 6 months of treatment negatively correlated with that of C4, and positively correlated with the baseline concentration of IgE and the IgG4/IgG ratio. Conclusion: IgG4-RDs are a group of diseases characterized by male predisposition; multiple organ involvement; a high eosinophil count; high IgE, IgG, IgG1, and IgG4 concentrations; and a low C3 concentration. Peripheral CD4+T cells and Treg cells are also more abundant. The diseases can be controlled with glucocorticoids and immunosuppressive drugs in the majority of instances. The IgG4 concentration after 6 months of treatment negatively correlates with the baseline complement C4 concentration and positively correlates with the IgE concentration and IgG4/IgG ratio, which suggests that IgG4/IgG, IgE, and complement should be closely monitored to evaluate disease activity and the efficacy of treatment in such patients.

Frequency of stress dosing and adrenal crisis in paediatric and adult patients with congenital adrenal hyperplasia: a prospective study.

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal crisis (AC) incidence, frequency, and details of SD and disease knowledge in adult and paediatric patients and their parents. DESIGN: Prospective, observational study. METHODS: Data on AC and SD were collected via a patient diary. In case of AC, medical records were reviewed and patient interviews conducted. Adherence to sick day rules of the German Society of Endocrinology (DGE) and disease knowledge using the German version of the CAH knowledge assessment questionnaire (CAHKAQ) were assessed. RESULTS: In 187 adult patients, the AC incidence was 8.4 per 100 patient years (py) and 5.1 in 100 py in 38 children. In adults, 195.4 SD episodes per 100 py were recorded, in children 169.7 per 100 py. In children 72.3% and in adults 34.8%, SD was performed according to the recommendations. Children scored higher on the CAHKAQ than adults (18.0 [1.0] vs 16.0 [4.0]; P = .001). In adults, there was a positive correlation of the frequency of SD and the incidence of AC (r = .235, P = .011) and CAHKAQ score (r = .233, P = .014), and between the incidence of AC and CAHKAQ (r = .193, P = .026). CONCLUSION: The AC incidence and frequency of SD in children and adults with CAH are high. In contrast to the paediatric cohort, the majority of SD in adults was not in accordance with the DGE recommendations, underlining the need for structured and repeated education of patients with particular focus on transition.

Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer.

BACKGROUND: The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC. METHODS: We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. RESULTS: In silico analyses combined with cell-based assays identified the Wnt-ß-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, ß-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. CONCLUSIONS: An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.

[Clinical study on growth impairment induced by oral glucocorticoids based on FGF23/Klotho homeostasis observations]. / 基于FGF23/Klothoç¨³æ€è§‚å¯Ÿå£æœç³–çš®è´¨æ¿€ç´ è‡´ç”Ÿé•¿éšœç¢çš„ä¸´åºŠç ”ç©¶.

OBJECTIVES: To observe the correlation between growth impairment induced by long-term oral glucocorticoids (GC) therapy and the ratio of FGF23/Klotho in children with primary nephrotic syndrome (PNS). METHODS: A prospective study was conducted on 56 children with GC-sensitive PNS who had discontinued GC therapy for more than 3 months and revisited the Department of Pediatrics of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine between June 2022 and December 2022. After monitoring qualitative and quantitative urine protein levels upon admission, the children with proteinuria relapse were treated with GC (GC group; n=29), while those without relapse did not receive GC treatment (non-GC group; n=27). In addition, 29 healthy children aged 3 to prepuberty were selected as the control group. Height, bone age, growth rate, and the FGF23/Klotho ratio were compared among the groups. The correlations of the FGF23/Klotho ratio with height, bone age, and growth rate were analyzed. RESULTS: The FGF23/Klotho ratio in the GC group was significantly higher than that in the non-GC group after 1 month of GC therapy (P<0.05), and the height and bone age growth rates within 6 months were lower than those in the non-GC group (P<0.05). Correlation analysis showed significant negative correlations between the FGF23/Klotho ratio after 1 month of treatment and the growth rates of height and bone age within 6 months in children with PNS (r=-0.356 and -0.436, respectively; P<0.05). CONCLUSIONS: The disturbance in FGF23/Klotho homeostasis is one of the mechanisms underlying the growth impairment caused by long-term oral GC therapy.

A novel mutation in the NR3C1 gene associated with reversible glucocorticoid resistance.

OBJECTIVE: Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GRR569Q) in a patient with uncommon reversible glucocorticoid resistance syndrome. METHODS: We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation. We studied the impact of the variant on the tertiary structure of the ligand-binding domain through 3D modeling. RESULTS: The patient presented initially with an adrenal adenoma with mild autonomous cortisol secretion and undetectable adrenocorticotropin hormone (ACTH) levels. Six months after surgery, biological investigations showed elevated cortisol and ACTH (urinary free cortisol 114 µg/24 h, ACTH 10.9 pmol/L) without clinical symptoms, evoking glucocorticoid resistance syndrome. Functional characterization of the GRR569Q showed decreased expression of target genes (in response to 100 nM cortisol: SGK1 control +97% vs patient +20%, P < .0001) and impaired nuclear translocation in patient fibroblasts compared to control. Similar observations were made in transiently transfected cells, but higher cortisol concentrations overcame glucocorticoid resistance. GRR569Q showed lower ligand affinity (Kd GRWT: 1.73 nM vs GRR569Q: 4.61 nM). Tertiary structure modeling suggested a loss of hydrogen bonds between H3 and the H1-H3 loop. CONCLUSION: This is the first description of a reversible glucocorticoid resistance syndrome with effective negative feedback on corticotroph cells regarding increased plasma cortisol concentrations due to the development of mild autonomous cortisol secretion.

Comparing the efficacy of glucocorticoids and anti-VEGF in treating diabetic macular edema: systematic review and comprehensive analysis.

Introduction: The aim of this study was to better understand the efficacy of various drugs, such as glucocorticoids and anti-vascular endothelial growth factors (VEGF), in the treatment of diabetic macular edema (DME), and to evaluate various clinical treatment regimens consisting of different therapeutic measures. Methods: This study included randomized controlled trials up to February 2023 comparing the efficacy of corticosteroid-related therapy and anti-VEGF therapy. PubMed, the Cochrane Library, and Embase were searched, and the quality of the studies was carefully assessed. Finally, 39 studies were included. Results: Results at 3-month followup showed that intravitreal injection of bevacizumab (IVB) + triamcinolone acetonide (TA) was the most beneficial in improving best-corrected visual acuity and reducing the thickness of macular edema in the center of the retina in patients with DME. Results at 6-month follow-up showed that intravitreal dexamethasone (DEX) was the most effective in improving patients' bestcorrected visual acuity and reducing the thickness of central macular edema. Discussion: Overall, IVB+TA was beneficial in improving best-corrected visual acuity and reducing central macular edema thickness over a 3-month follow-up period, while DEX implants had a better therapeutic effect than anti-VEGF agents at 6 months, especially the patients with severe macular edema and visual acuity impaired. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=397100, identifier CRD42023397100.

Corticosteroids for the prevention and treatment of bronchopulmonary dysplasia: an overview of systematic reviews.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD, explaining the rationale for investigating postnatal corticosteroids. Multiple systematic reviews (SRs) have summarised the evidence from numerous randomised controlled trials (RCTs) investigating different aspects of administrating postnatal corticosteroids. Besides beneficial effects on the outcome of death or BPD, potential short- and long-term harms have been reported. OBJECTIVES: The primary objective of this overview was to summarise and appraise the evidence from SRs regarding the efficacy and safety of postnatal corticosteroids in preterm infants at risk of developing BPD. METHODS: We searched the Cochrane Database of Systematic Reviews, MEDLINE, Embase, CINAHL, and Epistemonikos for SRs in April 2023. We included all SRs assessing any form of postnatal corticosteroid administration in preterm populations with the objective of ameliorating pulmonary disease. All regimens and comparisons were included. Two review authors independently checked the eligibility of the SRs comparing corticosteroids with placebo, and corticosteroids with different routes of administration and regimens. The included outcomes, considered key drivers in the decision to administer postnatal corticosteroids, were the composite outcome of death or BPD at 36 weeks' postmenstrual age (PMA), its individual components, long-term neurodevelopmental sequelae, sepsis, and gastrointestinal tract perforation. We independently assessed the methodological quality of the included SRs by using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) and ROBIS (Risk Of Bias In Systematic reviews) tools. We assessed the certainty of the evidence using GRADE. We provided a narrative description of the characteristics, methodological quality, and results of the included SRs. MAIN RESULTS: We included nine SRs (seven Cochrane, two non-Cochrane) containing 87 RCTs, 1 follow-up study, and 9419 preterm infants, investigating the effects of postnatal corticosteroids to prevent or treat BPD. The quality of the included SRs according to AMSTAR 2 varied from high to critically low. Risk of bias according to ROBIS was low. The certainty of the evidence according to GRADE ranged from very low to moderate. Early initiated systemic dexamethasone (< seven days after birth) likely has a beneficial effect on death or BPD at 36 weeks' PMA (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.81 to 0.95; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 41; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA (RR 0.72, 95% CI 0.63 to 0.82; NNTB 13, 95% CI 9 to 21; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence). Early initiated systemic hydrocortisone may also have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.90, 95% CI 0.82 to 0.99; NNTB 18, 95% CI 9 to 594; I2 = 43%; 9 studies; 1376 infants; low-certainty evidence). However, these benefits are likely accompanied by harmful effects like cerebral palsy or neurosensory disability (dexamethasone) or gastrointestinal perforation (both dexamethasone and hydrocortisone). Late initiated systemic dexamethasone (≥ seven days after birth) may have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; NNTB 5, 95% CI 4 to 9; I2 = 61%; 12 studies; 553 infants; low-certainty evidence), mostly contributed to by a beneficial effect on BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; NNTB 6, 95% CI 4 to 13; I2 = 14%; 12 studies; 553 infants; low-certainty evidence). No harmful side effects were shown in the outcomes chosen as key drivers to the decision to start or withhold late systemic dexamethasone. No effects, either beneficial or harmful, were found in the subgroup meta-analyses of late hydrocortisone studies. Early initiated inhaled corticosteroids probably have a beneficial effect on death and BPD at 36 weeks' PMA (RR 0.86, 95% CI 0.75 to 0.99; NNTB 19, 95% CI not applicable; I2 = 0%; 6 studies; 1285 infants; moderate-certainty evidence), with no apparent adverse effects shown in the SRs. In contrast, late initiated inhaled corticosteroids do not appear to have any benefits or harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier likely has a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.60, 95% CI 0.49 to 0.74; NNTB 4, 95% CI 3 to 6; I2 = 0%; 2 studies; 381 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA. No evidence of harmful effects was found. There was little evidence for effects of different starting doses or timing of systemic corticosteroids on death or BPD at 36 weeks' PMA, but potential adverse effects were observed for some comparisons. Lowering the dose might result in a more unfavourable balance of benefits and harms. Moderately early initiated systemic corticosteroids, compared with early systemic corticosteroids, may result in a higher incidence of BPD at 36 weeks' PMA. Pulse dosing instead of continuous dosing may have a negative effect on death and BPD at 36 weeks' PMA. We found no differences for the comparisons of inhaled versus systemic corticosteroids. AUTHORS' CONCLUSIONS: This overview summarises the evidence of nine SRs investigating the effect of postnatal corticosteroids in preterm infants at risk for BPD. Late initiated (≥ seven days after birth) systemic administration of dexamethasone is considered an effective intervention to reduce the risk of BPD in infants with a high risk profile for BPD, based on a favourable balance between benefits and harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is a promising intervention, based on the beneficial effect on desirable outcomes without (so far) negative side effects. Pending results of ongoing large, multicentre RCTs investigating both short- and long-term effects, endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is not appropriate for clinical practice at present. Early initiated (< seven days after birth) systemic dexamethasone and hydrocortisone and late initiated (≥ seven days after birth) hydrocortisone are considered ineffective interventions, because of an unfavourable balance between benefits and harms. No conclusions are possible regarding early and late inhaled corticosteroids, as more research is needed.

Analysis of the total serum IgE levels in patients with acute exacerbations chronic obstructive pulmonary disease: A retrospective study.

Currently, few studies have demonstrated the relationship between total serum IgE (T-IgE) and acute exacerbation chronic obstructive pulmonary disease (AECOPD). In this study, T-IgE in AECOPD patients were investigated and jointly analyzed with the clinical characteristics. AECOPD patients hospitalized from July 2018 to July 2019 were included in this study. In this patient cohort, clinical information was investigated. Routine blood tests, C-reactive protein and T-IgE levels of patients were determined along with blood gas analysis. The length of hospital stays, mechanical ventilation during hospitalization, ICU admission, glucocorticoid related clinical information were recorded. A total of 285 AECOPD patients were included in this study, which consisted of a high proportion of males. Of all patients, 49.82% patients exhibited higher T-IgE levels. Based on the reference T-IgE value 60 kU/L, patients were divided into high T-IgE group with T-IgE > 60 kU/L, and low T-IgE group with T-IgE ≤ 60 kU/L. There was no significant difference in the dosage of glucocorticoid between the two groups. Patients in the high T-IgE group had shorter hospital stays and lower probability of mechanical ventilation compared to the low T-IgE group. After adjustment for confounding factors, T-IgE was negatively correlated with the length of hospital stays. AECOPD patients with elevated T-IgE had shorter hospital stays and lower risks of mechanical ventilation and ICU admission. Our results showed that T-IgE might play an important role on evaluating the condition and guiding for treatment decisions in AECOPD patients.

A retrospective study of combination therapy with glucocorticoids and pirfenidone for PD-1 inhibitor-related immune pneumonitis.

Immune checkpoint inhibitor pneumonitis (ICIP) is thought to be a self-limiting disease; however, an effective treatment option does not currently exist. This study aimed to determine the clinical efficacy of combination therapy with glucocorticoids and pirfenidone for ICIP related to programmed cell death protein-1 (PD-1) inhibitors. We conducted a retrospective analysis of 45 patients with advanced non-small cell lung cancer who developed ICIP following PD-1 inhibitor and albumin-bound paclitaxel or carboplatin treatment at our hospital. The PD-1 inhibitor was discontinued, and glucocorticoids were used alone or in combination with pirfenidone to treat ICIP. The relevant clinical data of these patients were collected and analyzed. Compared with the glucocorticoid alone group, the glucocorticoid-pirfenidone group showed significant improvement in forced vital capacity (FVC), carbon monoxide diffusing capacity [%], peripheral capillary oxygen saturation, and 6-minute walk distance (P < .05). There were benefits with respect to the St. George's Respiratory Questionnaire score and the recurrence rate of ICIP, but there was no significant difference between the 2 groups (P > .05). Adding pirfenidone to glucocorticoid treatment was shown to be safe and may be more beneficial than glucocorticoids alone for improving pulmonary interstitial lesions, reversing ICIP, and preventing its recurrence.

Levamisole in childhood idiopathic nephrotic syndrome: new promises, and advocacy for global access.

In the current issue of Kidney International, Sinha et al. present data from an open-label, noninferior, randomized controlled trial comparing 12-months of alternate-day prednisolone, given daily during infection, versus levamisole, in children with frequently relapsing or steroid-dependent nephrotic syndrome. This study suggests that both of these strategies are efficacious and safe. Results of this study should redefine the role of levamisole in future guidelines, and a call for global availability of levamisole should be advocated.

Impact of glucocorticoids and rapamycin on autophagy in Candida glabrata-infected macrophages from BALB/c mice.

Objective: In the defense against microorganisms like Candida albicans, macrophages recruit LC3(Microtubule-associated protein 1A/1B-light chain 3) to the periplasm, engaging in the elimination process through the formation of a single-membrane phagosome known as LC3-associated phagocytosis (LAP). Building on this, we propose the hypothesis that glucocorticoids may hinder macrophage phagocytosis of Candida glabrata by suppressing LAP, and rapamycin could potentially reverse this inhibitory effect. Methods: RAW264.7 cells were employed for investigating the immune response to Candida glabrata infection. Various reagents, including dexamethasone, rapamycin, and specific antibodies, were utilized in experimental setups. Assays, such as fluorescence microscopy, flow cytometry, ELISA (Enzyme-Linked Immunosorbent Assay), Western blot, and confocal microscopy, were conducted to assess phagocytosis, cytokine levels, protein expression, viability, and autophagy dynamics. Results: Glucocorticoids significantly inhibited macrophage autophagy, impairing the cells' ability to combat Candida glabrata. Conversely, rapamycin exhibited a dual role, initially inhibiting and subsequently promoting phagocytosis of Candida glabrata by macrophages. Glucocorticoids hinder macrophage autophagy in Candida glabrata infection by suppressing the MTOR pathway(mammalian target of rapamycin pathway), while the activation of MTOR pathway by Candida glabrata diminishes over time. Conclusion: Our study elucidates the intricate interplay between glucocorticoids, rapamycin, and macrophage autophagy during Candida glabrata infection. Understanding the implications of these interactions not only sheds light on the host immune response dynamics but also unveils potential therapeutic avenues for managing fungal infections.

Monitoring adrenal insufficiency through salivary steroids: a pilot study.

BACKGROUND: Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires. METHODS: Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis. RESULTS: Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores. CONCLUSIONS: None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality.

Clinical Evaluation of the Child with Eosinophilic Esophagitis.

The diagnosis of eosinophilic esophagitis (EoE) is based on clinical symptoms of esophageal dysfunction and eosinophil predominant esophageal inflammation. Clinical symptoms in children with EoE vary based on age and may be nonspecific. EoE has a male predominance with the majority having comorbid atopic disorders. At present, treatment options include medications (proton pump inhibition, swallowed topical steroids), dietary therapy or biologic therapy (dupilumab, approved for those ≥12 years of age). Outside of EoE in the context of oral immunotherapy, EoE is typically chronic requiring lifelong therapy. Long-term complications including feeding difficulties, malnutrition, and fibrostenotic disease.