Corticosteroid Response Research Articles

Predicting corticosteroid response in COPD using baseline bronchial biopsy DNA methylation

Predicting corticosteroid response in COPD using baseline bronchial biopsy DNA methylation

Impact of Karnofsky performance status on outcomes of patients with severe alcohol-associated hepatitis: a propensity-matched analysis.

Severity scores, including the model for end-stage liver disease (MELD) and discriminant function score, guide the treatment of patients with severe alcohol-associated hepatitis (AH). We aimed to investigate the impact of functional status on outcomes of patients with AH. Medically managed patients (n = 133) with AH from 1 January 2019 to 31 December 2022 were included in this prospective study. The objectives were to compare the long-term survival, recompensation rates, corticosteroid response, incidence of infections, hepatic encephalopathy (HE) and acute kidney injury (AKI) among propensity score-matched patients with good Karnofsky performance status (KPS) (score ≥50) and poor KPS (score <50) using Kaplan-Meier analysis. Twenty-five patients with good KPS were matched with 25 patients with poor KPS and followed up for a median duration of 10 (0.5-33) months. Survival was 76% (19/25; 95% confidence interval (CI), 54.9-90.6) in patients with good KPS compared to 42.3% (11/25; 95% CI, 23.4-63.1) patients with poor KPS (P = 0.001) at 10 months. The recompensation rate was higher in the good KPS group than in the poor KPS group (68% vs 44%; P = 0.04). A higher proportion of patients in the good KPS group (78.9%) than in the poor KPS group (42.8%; P = 0.03) responded to corticosteroids. Survival was lower among non-responders in the poor KPS group (0% vs 75%; P = 0.01). The proportion of patients who developed infection (36% vs 28%; P = 0.051), HE (36% vs 12%; P = 0.01) and AKI (60% vs 16%; P < 0.001) was higher in patients with poor KPS than in good KPS. KPS is an important determinant of outcomes in patients with AH, including survival, recompensation, response to corticosteroids and complications.

Prognostic Value of CRP/25 OH Vitamin D Ratio for Glucocorticoid Efficacy in Acute Severe Ulcerative Colitis Patients.

Introduction: Acute severe ulcerative colitis (ASUC) represents a life-threatening medical emergency. One-third of ASUC patients are steroid non-responders. Our study aimed to create a new ASUC algorithm to predict corticosteroid response in the early course of the disease. Materials and Methods: A cross-sectional study included 103 patients with ASUC (65 male, 38 female). We calculated the serum CRP to 25-hydroxy 25 OH vitamin D ratio at admission. Logistic regression determined patients' response to glucocorticoids, depending on the CRP/25 OH vitamin D ratio value. Results and Discussion: Significant differences were observed in the CRP/25 OH vitamin D ratio at admission between glucocorticoid responders and non-responders (p = 0.001). A negative correlation was found between glucocorticoid response and CRP/25 OH vitamin D levels (Spearman's rho = -0.338, p < 0.01). Logistic regression revealed a significant association (p = 0.003) with a model chi-square value of 11.131 (p = 0.001). ROC curve analysis showed an AUC of 0.696 (p = 0.001), indicating moderate discriminatory ability. To achieve 91% sensitivity, the CRP/25 OH vitamin D ratio must be less than 3.985 to predict a complete glucocorticoid response. Conclusions: The serum CRP to 25 OH vitamin D ratio on the first day of hospital admission can potentially determine the response to glucocorticoids in patients with ASUC and significantly affect the mortality of these patients.

Genome-Wide Association Studies of Pediatric Nephrotic Syndrome Identify Variants Associated with Corticosteroid Response

Genome-Wide Association Studies of Pediatric Nephrotic Syndrome Identify Variants Associated with Corticosteroid Response

Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19

BackgroundThe effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. MethodsThe comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FindingsThe demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19. InterpretationCritical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.

Rethinking Blood Eosinophils for Assessing Inhaled Corticosteroids Response in COPD: A Post Hoc Analysis From the FLAME Trial

BackgroundThe varied treatment response to inhaled corticosteroids (ICS) in COPD, and the increased risk of pneumonia necessitate a personalised ICS therapeutic approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. However, BEC appears to change in response to ICS treatment. Research questionDoes BEC measured on or off ICS treatment or the change in BEC during ICS treatment, best predict treatment response to ICS in COPD? Study design and methodsFLAME, a 52-week, double-blind RCT compared LABA/LAMA versus LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing pre- and post-run-in period BEC to represent BEC on and off ICS, respectively. In this post-hoc analysis, we revisited outcome data, exploring how the three BEC biomarkers interacted with treatment response to the ICS containing regimen. ResultsOur study confirms that LABA/LAMA combination is superior, or at least non-inferior, to LABA/ICS in curbing exacerbations for most FLAME participants. However, higher BEC off and BEC on ICS and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of exacerbation rate, time-to-first exacerbation, and time-to-first pneumonia. In a subgroup, including 9% of participants, BEC changed significantly during ICS treatment (≥200 cells/μL), and higher BEC on ICS did not predict ICS treatment response. For these patients, BEC off ICS and BEC change proved more predictive. Excess pneumonia risk associated with ICS appeared to be confined to patients who do not benefit from this treatment. BEC were not predictive of treatment effects on lung function and health status. InterpretationThis exploratory analysis advocates preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. BEC measured on ICS is less predictive of treatment response. Clinical trial registrationNCT01782326

Role of FeNO in predicting the responsiveness of inhaled corticosteroids in COPD: a systematic review.

Fractional exhaled nitric oxide (FeNO) as a predictor of inhaled corticosteroid (ICS) response in asthma has been established. However, the same has not been established in chronic obstructive pulmonary disease (COPD). An optimal value of FeNO for prescribing and monitoring ICS response has not been quantified. To examine the evidence for this association. A systematic review was conducted of randomised controlled trials and observational studies examining the association between FeNO level and response to ICS in COPD patients. All studies examining this association were included. Five databases were searched thoroughly. Systematic screening, full-text reviews, and data extraction were carried out based on eligibility criteria. A total of 8690 studies were identified, 342 texts were screened fully, and six studies were included for the final review. One was a randomised controlled trial and the other five were non-randomised interventional trials. One study was conducted in asthma-COPD overlap (ACO patients). After ICS use, three studies found statistically significant correlations between FeNO and lung function improvement (FEV1), and three studies also found significant correlations between FeNO and COPD quality-of-life scores. Measurement of FeNO is non-invasive and standardised, with results available at the point of testing. Because of the small sample size and short duration of studies, exacerbation frequencies were not measured. Despite this, the review suggests that FeNO may be a potential biomarker for assessing ICS response in COPD. Further research that stratifies patients by FeNO levels and assesses the impact on acute exacerbations is needed to understand its potential value in routine clinical practice.

Association of blood eosinophils with corticosteroid treatment failure stratified by smoking status among inpatients with AECOPD

BackgroundRecent studies have suggested elevated blood eosinophils are independent predictors of response to corticosteroid therapy in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Smoking status has been...

GSDMB/ORMDL3 Rare/Common Variants Are Associated with Inhaled Corticosteroid Response among Children with Asthma.

Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response (DPP10, FBXL7, NDFIP1, TBXT, GLCCI1, HDAC9, TBXAS1, STAT6, GSDMB/ORMDL3, CRHR1, GNGT2, FCER2), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), GSDMB/ORMDL3 was significantly associated with ICS response for the combined effect of rare and common variants (p-value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative (p-value = 0.02). Using WES data, the combined effect of rare and common variants for GSDMB/ORMDL3 was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations.

Transcriptomic profiling of osteoarthritis synovial macrophages reveals a tolerized phenotype compounded by a weak corticosteroid response.

It is well-known that long-term osteoarthritis prognosis is not improved by corticosteroid treatments. Here we investigate what could underlie this phenomenon by measuring the short term corticosteroid response of OA-Mf. We determined the genome-wide transcriptomic response to corticosteroids of end-stage osteoarthritic joint synovial macrophages (OA-Mf). This was compared with LPS-tolerized and β-glucan-trained circulating blood monocyte-derived macrophage models. Upon corticosteroid stimulation, the trained and tolerized macrophages significantly alter the abundance of 201 and 257 RNA transcripts, respectively. By contrast, by the same criteria, OA-Mf have a very restricted corticosteroid response of only 12 RNA transcripts. Furthermore, while metalloproteinases 1, -2, -3 and -10 expression clearly distinguish OA-Mf from both the tolerized and trained macrophage models, OA-Mf Interleukin 1 (IL1), chemokine (CXCL) and cytokine (CCL) family member profiles resemble the tolerized macrophage model, with the exception that OA-Mf show high levels of CCL20. Terminal osteoarthritis joints therefore harbor macrophages with an inflammatory state that closely resembles the tolerized macrophage state and this is compounded by a weak corticosteroid response capacity that may explain the lack of positive long-term effects of corticosteroid treatment for osteoarthritis patients.

Assessing Inhaled Corticosteroid Adherence and Responsiveness in Severe Asthma Using Beclometasone Dipropionate/Formoterol NEXThaler Dose-Counting and Nitric Oxide Monitoring

65% of people with severe asthma and a FeNO ≥45 ppb are non-adherent to inhaled corticosteroids (ICS). Digital devices recording both time-of-use and inhaler technique identify non-adherence and ICS responsiveness but are not widely available. As the NEXThaler™ dose counter only activates at an inspiratory flow of 35 L/min, this may provide an alternative to identifying ICS responsiveness. To assess ICS adherence and responsiveness in severe asthma using beclometasone/formoterol (200/6 mcg) NEXThaler™ (BFN) dose-counting. Severe asthmatics with a FeNO ≥45 ppb were invited to use BFN in place of their usual ICS/long-acting β2-agonist (LABA). FeNO, ACQ6, lung function and blood eosinophil count were monitored for 3 months. A log10ΔFeNO ≥0.24 was used to define FeNO suppression as the primary marker of ICS responsiveness at day 28. 27/48 (56%) patients demonstrated significant FeNO suppression at month 1 (median pre-114, post-48 ppb, p<0.001). A small but significant reduction occurred in FeNO non-suppressors. ACQ6 fell a median 1.2 units in FeNO suppressors (p<0.001) and 0.5 units in non-suppressors (p=0.025). These effects were sustained until month 3 in FeNO suppressors with a significant improvement in FEV1 and blood eosinophils. 67% (18/27) of those with baseline ICS/LABA prescription refills of ≥80% were FeNO suppressors suggesting prior non-adherence despite adequate prescription collection. 79% of FeNO suppressors did not require biologics within mean 11.4 months from initial dose counting. BFN dose counting identifies ICS responsiveness in severe asthma with the implication that these patients may not need to progress to biological therapies.

ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.

Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Exploratory Review of the Takotsubo Syndrome and the Possible Role of the Psychosocial Stress Response and Inflammaging.

Takotsubo syndrome (TTS) is a cardiomyopathy that clinically presents as a transient and reversible left ventricular wall motion abnormality (LVWMA). Recovery can occur spontaneously within hours or weeks. Studies have shown that it mainly affects older people. In particular, there is a higher prevalence in postmenopausal women. Physical and emotional stress factors are widely discussed and generally recognized triggers. In addition, the hypothalamic-pituitary-adrenal (HPA) axis and the associated glucocorticoid-dependent negative feedback play an important role in the resulting immune response. This review aims to highlight the unstudied aspects of the trigger factors of TTS. The focus is on emotional stress/chronic unpredictable mild stress (CUMS), which is influenced by estrogen concentration and noradrenaline, for example, and can lead to changes in the behavioral, hormonal, and autonomic systems. Age- and gender-specific aspects, as well as psychological effects, must also be considered. We hypothesize that this leads to a stronger corticosteroid response and altered feedback of the HPA axis. This may trigger proinflammatory markers and thus immunosuppression, inflammaging, and sympathetic overactivation, which contributes significantly to the development of TTS. The aim is to highlight the importance of CUMS and psychological triggers as risk factors and to make an exploratory proposal based on the new knowledge. Based on the imbalance between the sympathetic and parasympathetic nervous systems, transcutaneous vagus nerve stimulation (tVNS) is presented as a possible new therapeutic approach.

P869 Deep ulcers in acute Ulcerative Colitis at index endoscopy predict corticosteroid resistance

Abstract Background Ulcerative Colitis (UC) is a chronic inflammatory disease affecting the colon. Its acute form can be life-threatening, necessitating hospital admission and intravenous (IV) corticosteroid treatment. This study aimed to predict IV corticosteroid response in acute UC patients based on endoscopic findings at admission. Methods Individuals admitted to the hospital for acute UC for intravenous corticosteroid treatment were selected. Those with gastrointestinal infections and those without endoscopy at admission were excluded. Results A retrospective analysis was conducted on a cohort of 62 patients, of which 25.8% did not respond to IV steroids. No significant associations were found between demographic, clinical, and laboratory parameters and corticosteroid response at admission. Rectosigmoidoscopy was performed for all patients upon hospitalization, and the Mayo Endoscopic Score (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) were obtained. The results revealed significant differences in median UCEIS scores between non-responders and responders (7, IQR 3 vs. 5, IQR 1, p=0.011). Notably, a UCEIS score of ≥5 demonstrated a sensitivity of 100% in identifying patients who did not respond to corticosteroids, although with a lower specificity of 22.7%. Furthermore, the MES exhibited a statistically significant association with treatment response (p=0.002), with a MES≤2 having a negative predictive value of 92.9% for IV steroid resistance. Importantly, the presence and type (small vs. large) of ulcers at the initial endoscopy were found to be the most effective predictive factor for corticosteroid response (AUC=0.745; 95%CI=0.594-0.896; p=0.005), as 57.1% of patients with deep ulcers were non-responders. Conclusion The importance of evaluating ulcer severity during endoscopic assessment in patients with acute ulcerative colitis is underscored by our findings. Notably, the presence of deep mucosal ulcerations should prompt consideration for intensifying therapy.

OP09 Oral ritlecitinib and brepocitinib in patients with moderate to severe active Crohn’s Disease: Data from the PIZZICATO umbrella study

Abstract Background Oral ritlecitinib (RIT; JAK3/TEC family kinase inhibitor) and brepocitinib (BRE; TYK2/JAK1 inhibitor) are being assessed in a 64-week (wk) phase 2a randomised, double-blind, induction-maintenance, umbrella study (PIZZICATO; NCT02958865) in participants (pts) with moderate-to-severe active Crohn’s disease (CD) with inadequate, loss of response or intolerance of corticosteroids, immunosuppressants or biologics. We report the efficacy and safety results from the 12-wk induction period. Methods Pts 18-75 years old with endoscopic confirmation of active CD with Simple Endoscopic Score for CD (SES-CD) ≥7/≥4 for isolated ileal disease, and average daily liquid/soft stool frequency (SF) ≥2.5 or daily abdominal pain (AP) ≥2.0 were included. Pts were randomised to RIT 200 mg once daily (QD) for 8 wks then 50 mg QD for 4 wks and matching placebo (PBO) in a 2:1 ratio or BRE 60 mg QD for 12 wks and matching PBO in a 2:1 ratio. Pts continued in their respective arms with open-label RIT 50 mg or BRE 30 mg QD for 52 wks. PBO arms were combined for analysis. Pts achieving SES-CD 50 (≥50% reduction in SES-CD from baseline [BL]; primary endpoint Wk 12), Clinical Disease Activity Index (CDAI) remission (CDAI&amp;lt;150) and CDAI-100 response for pts with BL CDAI≥220, clinical response (≥30% reduction from BL in AP or SF; neither worse than BL) and remission (SF≤1.5 and AP≤1; neither worse than BL) were assessed. Safety was also evaluated. Results A total of 244 pts were randomised and received treatment in the induction period with BL mean age of 34.6-36.5 years, median SES-CD 11-14, and prior biologics experience 69-76% across groups. The proportion of pts achieving SES-CD 50 was significantly higher at Wk 12 with RIT 200/50 mg QD and BRE 60 mg vs PBO (change from PBO: RIT 14.3% [90% CI, 4.0, 24.5], BRE 21.4% [10.0, 32.9]; Table). Statistical significance vs PBO was observed for RIT at Wks 8 and 12 and BRE at Wk 12 for CDAI remission, CDAI-100, clinical response and remission by SF or AP. Most treatment emergent adverse events (TEAEs) in both groups were mild or moderate. Herpes infections occurred in 1 pt in each group and serious infections in 1 pt in RIT and 2 in BRE. No deaths or malignancies occurred. No events of thromboembolism or MACE occurred for RIT. One pt on BRE had a TEAE of pulmonary embolism. There were no clinically significant observations for labs. Conclusion Both RIT and BRE met the primary endpoint in the induction period with significant clinical improvement vs PBO in pts with active CD. Other meaningful efficacy endpoints had similar results to the primary endpoint for both therapies. RIT and BRE had an acceptable safety and tolerability profile that was consistent with previous studies.

Corticosteroid sensitivity detection in sepsis patients using a personalized data mining approach: A clinical investigation

Background and ObjectiveSepsis is a life-threatening disease with high mortality, incidence, and morbidity. Corticosteroids (CS) are a recommended treatment for sepsis, but some patients respond negatively to CS therapy. Early prediction of corticosteroid responsiveness can help intervene and reduce mortality. In this study, we aim to develop a data mining methodology for predicting CS responsiveness of septic patients. MethodsWe used data from a randomized controlled trial called APROCCHSS, which recruited 1241 septis patients to study the effectiveness of corticotherapy. We conducted a thorough study of multiple machine learning models to select the most efficient prediction model, called “signature”. We evaluated the performance of the signature using precision, sensitivity, and specificity values. ResultsWe found that Logistic Regression was the best model with an AUC of 72%. We conducted further experiments to examine the impact of additional features and the model's generalizability to different groups of patients. We also performed a statistical analysis to analyze the effect of the treatment at the individual level and on the population as a whole. ConclusionsOur data mining methodology can accurately predict cortico-sensitivity or resistance in septis patients. The signature has been deployed into the Assistance Publique – Hôpitaux de Paris (APHP) information system as a web service, taking patient information as input and providing a prediction of cortico-sensitivity or resistance. Early prediction of corticosteroid responsiveness can help clinicians intervene promptly and improve patient outcomes.

The utility of biomarkers to predict steroid response in idiopathic nephrotic syndrome

Objective: The most common form of nephrotic syndrome (NS) is minimal change disease (MCD) in children and focal segmental glomerulosclerosis (FSGS) following it. As, it is important to predict corticosteroid (CS) response at the beginning of the disease, we aimed to evaluate the efficacy of some biomarkers in terms of predicting steroid response in patients with NS. Patients and Methods: Twenty patients who met the inclusion criteria for the study were divided into 3 groups and 6 healthy control participants were included in the analysis as the 4th group. Group-1 included 10 patients at the first episode of idiopathic NS (INS), group-2 included the same 10 patients in remission, group-3 included 10 patients with steroid resistant NS (SRNS) diagnosed as FSGS by renal biopsy, and group-4 included six healthy children as controls. Urinary and serum cluster of differentiation (CD) CD80, IL-17, IL-23, IL-10, TGF-β, CD86, CD28, CTLA-4 levels were measured for all groups. Results: Urinary CD80 level in INS-relapse group was significantly higher than the levels of the INS-remission, FSGS and control groups (p

Myeloid spatial and transcriptional molecular signature of ischemia-reperfusion injury in human liver transplantation.

Ischemia-reperfusion injury (IRI) is a significant clinical concern in liver transplantation, with a key influence on short-term and long-term allograft and patient survival. Myeloid cells trigger and sustain tissue inflammation and damage associated with IRI, but the mechanisms regulating these activities are unknown. To address this, we investigated the molecular characteristics of intragraft myeloid cells present in biopsy-proven IRI- and IRI+ liver transplants. RNA-sequencing was performed on 80 pre-reperfusion and post-reperfusion biopsies from 40 human recipients of liver transplantation (23 IRI+, 17 IRI-). We used transcriptional profiling and computational approaches to identify specific gene coexpression network modules correlated with functional subsets of MPO+, lysozyme+, and CD68+ myeloid cells quantified by immunohistochemistry on sequential sections from the same patient biopsies. A global molecular map showed gene signatures related to myeloid activation in all patients regardless of IRI status; however, myeloid cell subsets differed dramatically in their spatial morphology and associated gene signatures. IRI- recipients were found to have a natural corticosteroid production and response profile from pre-reperfusion to post-reperfusion, particularly among monocytes/macrophages. The pre-reperfusion signature of IRI+ recipients included acute inflammatory responses in neutrophils and increased translation of adaptive immune-related genes in monocytes/macrophages coupled with decreased glucocorticoid responses. Subsequent lymphocyte activation at post-reperfusion identified transcriptional programs associated with the transition to adaptive immunity found only among IRI+ recipients. Myeloid subset-specific genes and related signaling pathways provide targets for the development of therapeutic strategies aimed at limiting IRI in the clinical setting of liver transplantation.

Immune thrombocytopenia (ITP) with corticosteroids: “Evaluation of Response”

Objective: to evaluate the response of corticosteroids in newly persistent ITP patients. Methodology: Descriptive Case series conducted from 30th October 20202 to 29th April 2021 at Armed Forces Bone Marrow Transplant Centre Rawalpindi. A total of 74 individuals with ITP who were both males and females of various ages. Prednisolone was administered orally to patients in maximal dose of 1mg/kg. The initial reaction of platelets count was assessed on day 5 and subsequently every two weeks until the full response was attained. An informed consent was obtained. Results: Age was 32.0±19.1 years on average. Twenty-four (32.4%) of the patients were over the age of 40 while the majority (n=50, 67.6%) of the patients were under the age of 40 years. There were 1:1.1 patients that were male and female with 36 (48.6%) men and 38(51.4%) women. Twenty (27.0%) individuals had persistent ITP compared to 54 (73.0%) patients who had just been diagnosed. 34 (45.9%) patients had an initial response whereas 43 patients (58.1%) showed a full response. The average initial response time was 5.47±2.39 days and 11.79±6.73 days for full response. The frequency of first didn’t differ statistically significantly by patient age, gender or other subgroups. Conclusion: Regardless of age, gender, or ITP type, steroids were associated with an initial and complete response in a significant majority of patients with immune thrombocytopenia. Keeping in view with their affordability accessibility favors the use of steroids as first line in these patients.

Weight loss and vitamin D improve hyporesponsiveness to corticosteroids in obese asthma.

Obesity negatively impacts on asthma response to inhaled corticosteroids by unknown mechanisms. Objective: To demonstrate that the poor response to inhaled corticosteroids in obese asthma is associated with an impaired anti-inflammatory activity of corticosteroids and vitamin D deficiency, both improved by weight loss. 23 obese asthmatics (OA) [18 females; median age (interquartile range) 56 (51-59) years], 14 non-obese asthmatics (NOA) [11 females; 53 (43-60) years], 15 obese (O) [13 females; 47 (45-60) years], and 19 healthy controls (HC) [14 females; 43 (34-56) years] were enrolled. 10 OA and 11 O patients were evaluated at baseline (V1) and six months after (V2) bariatric surgery. Corticosteroid response was measured by dexamethasone inhibition of peripheral blood mononuclear cell (PBMC) proliferation. Lung function, serum levels of leptin, adiponectin, and vitamin D were measured at V1 and V2. We found a reduced response to dexamethasone in PBMCs of O and OA patients with respect to NOA and HC subjects, that inversely correlated with the diponectin/leptin ratio and vitamin D levels. Bariatric surgery improved corticosteroid responses in O and OA patients and normalized adiponectin/leptin ratio and vitamin D levels. Exposure of PBMCs to vitamin D potentiated the antiproliferative effects of corticosteroids. Dexamethasone and vitamin D induced similar MKP-1 expression in O and OA patients. We found a reduced response to dexamethasone in PBMCs of O and OA patients with respect to NOA and HC subjects, that inversely correlated with the adiponectin/leptin ratio and vitamin D levels. Bariatric surgery improved corticosteroid responses in O and OA patients and normalized adiponectin/leptin ratio and vitamin D levels. Exposure of PBMCs to vitamin D potentiated the antiproliferative effects of corticosteroids. Dexamethasone and vitamin D induced similar MKP-1 expression in O and OA patients.