Inhaled glucocorticoids are the recommended treatment for persistent childhood asthma. In a randomized, controlled trial, the use of inhaled budesonide in childhood was associated with a decrease of ...1.2 cm in attained adult height, as compared with placebo.
Inhaled glucocorticoids are the recommended therapy for persistent asthma in children.
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In prepubertal children, however, the use of inhaled glucocorticoids has been shown to reduce growth velocity, resulting in a linear growth reduction of 0.5 to 3.0 cm (approximately 1 cm on average) during the first few years of therapy.
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This reduction has been reported for low-to-medium doses, but the degree of reduction is dependent on the type of inhaled glucocorticoid and the delivery method.
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Although growth velocity returns to normal within a few years after the initiation of inhaled glucocorticoid therapy (resulting in a deficit in height . . .
A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to ...normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a study involving patients with nonalcoholic fatty liver disease, all-cause mortality over a median of 4 years was higher among patients with advanced fibrosis at baseline than among those with ...lower fibrosis stages. Advanced fibrosis was related to an increased incidence of liver decompensation events.
Vibration‐controlled transient elastography estimates liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), which are noninvasive assessments of hepatic fibrosis and ...steatosis, respectively. However, prior vibration‐controlled transient elastography studies reported high failure rates in patients with nonalcoholic fatty liver disease. We examined the performance characteristics of the FibroScan 502 Touch with two probes, medium (M+) and extra large (XL+), in patients with nonalcoholic fatty liver disease in a multicenter setting. A total of 1,696 exams were attempted in 992 patients (body mass index, 33.6 ± 6.5 kg/m2) with histologically confirmed nonalcoholic fatty liver disease. Simultaneous assessment of LSM and CAP was performed using the FibroScan 502 Touch with an automatic probe selection tool. Testing was conducted twice in patients by either a single operator (87%) or two operators (13%). Failure was defined as the inability to obtain a valid examination. An examination was considered unreliable if LSM interquartile range/median was >30%. Significant disagreement between two readings was defined as >95% limits of agreement between two readings. A total of 1,641 examinations yielded valid results with a failure rate of 3.2% (55/1,696). The proportion of unreliable scans for LSM was 3.9%. The proportion of unreliable scans with operator experience in the top quartile (≥59 procedures) was significantly lower than that in the lower three quarters combined (1.6% versus 4.7%, P = 0.02 by Fisher's exact test). The significant disagreement between first and second readings for LSM and CAP when obtained back to back was 18% and 11%, respectively. Conclusion: Vibration‐controlled transient elastography for estimation of LSM and CAP can be successfully deployed in a multicenter setting with low failure (3.2%) and high reliability (>95%) rates and high reproducibility. (Hepatology 2018;67:134‐144).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Vibration-controlled transient elastography (VCTE), which measures liver stiffness, has become an important tool for evaluating patients with nonalcoholic fatty liver disease (NAFLD). We aimed to ...determine the diagnostic accuracy of VCTE in detection of NAFLD in a multicenter cohort of patients.
We performed a prospective study of 393 adults with NAFLD who underwent VCTE within 1 year of liver histology analysis (median time, 49 d; interquartile range, 25-78 d), from July 1, 2014, through July 31, 2017. Liver stiffness measurement (LSM) cut-off values for pairwise fibrosis stage and controlled attenuation parameter cut-off values for pairwise steatosis grade were determined using cross-validated area under the receiver operating characteristics curve (AUROC) analyses. Diagnostic statistics were computed at a sensitivity fixed at 90% and a specificity fixed at 90%.
LSM identified patients with advanced fibrosis with an AUROC of 0.83 (95% CI, 0.79- 0.87) and patients with cirrhosis with an AUROC of 0.93 (95% CI, 0.90-0.97). At a fixed sensitivity, a cut-off LSM of 6.5 kPa excluded advanced fibrosis with a negative predictive value of 0.91, and a cut-off LSM of 12.1 kPa excluded cirrhosis with a negative predictive value of 0.99. At a fixed specificity, LSM identified patients with advanced fibrosis with a positive predictive value of 0.71 and patients with cirrhosis with a positive predictive value of 0.41. Controlled attenuation parameter analysis detected steatosis with an AUROC of 0.76 (95% CI, 0.64-0.87). In contrast, the VCTE was less accurate in distinguishing lower fibrosis stages, higher steatosis grades, or the presence of NASH.
In a prospective study of adults with NAFLD, we found VCTE to accurately distinguish advanced vs earlier stages of fibrosis, using liver histology as the reference standard.
Abstract Background & Aims We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis ...in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. Methods We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed. Results At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0–1 vs 2–3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91–0.98), and grade 0–2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93–0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2–3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs. placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71–0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63–0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity. Conclusions Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference.
Background. While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains ...unclear. Methods. We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4⁺ T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency. Results. Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4⁺ T-cell count (all P ≤001). A higher percentage of CD38⁺HLA-DR⁺ cells in the CD8⁺ T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4⁺ T-cell count. Frequencies of senescent (defined as CD28⁻CD57⁺ cells), exhausted (defined as PD1⁺ cells), naive, and CMV-specific T cells did not predict mortality. Conclusions. Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation—but not T-cell activation, senescence, and exhaustion—independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Systemic corticosteroids are known to induce osteoporosis and increase the risk for fractures in adults and children. Inhaled corticosteroids have been shown to increase the risk for osteoporosis and ...fractures in adults at risk; however, long-term prospective studies of children to assess risks of multiple short courses of oral corticosteroids and chronic inhaled corticosteroids have not been performed. Thus, we assessed the effects of multiple short courses of oral corticosteroids and long-term inhaled corticosteroids on bone mineral accretion over a period of years.
This was a cohort follow-up study for a median of 7 years of children who had mild-to-moderate asthma and initially were randomly assigned into the Childhood Asthma Management Program trial. Serial dual-energy radiograph absorptiometry scans of the lumbar spine for bone mineral density were performed for all patients. Annual bone mineral accretion was calculated for 531 boys and 346 girls who had asthma and were aged 5 to 12 years at baseline (84% of the initial cohort).
Oral corticosteroid bursts produced a dosage-dependent reduction in bone mineral accretion (0.052, 0.049, and 0.046 g/cm(2) per year) and an increase in risk for osteopenia (10%, 14%, and 21%) for 0, 1 to 4, and >or=5 courses, respectively, in boys but not girls. Cumulative inhaled corticosteroid use was associated with a small decrease in bone mineral accretion in boys but not girls but no increased risk for osteopenia.
Multiple oral corticosteroid bursts over a period of years can produce a dosage-dependent reduction in bone mineral accretion and increased risk for osteopenia in children with asthma. Inhaled corticosteroid use has the potential for reducing bone mineral accretion in male children progressing through puberty, but this risk is likely to be outweighed by the ability to reduce the amount of oral corticosteroids used in these children.
Nonalcoholic Fatty Liver Disease. Reply Sanyal, Arun J; Van Natta, Mark L; Tonascia, James
The New England journal of medicine,
01/2022, Volume:
386, Issue:
3
Journal Article
IMPORTANCE Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials. Tricyclic antidepressants are often used to treat ...refractory symptoms of nausea, vomiting, and abdominal pain. Evidence from well-designed studies for this use is lacking. OBJECTIVE To determine whether treatment with nortriptyline results in symptomatic improvement in patients with idiopathic gastroparesis. DESIGN, SETTING, AND PARTICIPANTS The NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, a 15-week multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC), comparing nortriptyline with placebo for symptomatic relief in idiopathic gastroparesis. One hundred thirty patients with idiopathic gastroparesis were enrolled between March 2009 and June 2012 at 7 US academic medical centers. Patient follow-up was completed in October 2012. Inclusion criteria included delayed gastric emptying and moderate to severe symptom scores using the Gastroparesis Cardinal Symptom Index (GCSI). INTERVENTIONS Nortriptyline vs placebo. Study drug dose was increased at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome measure of symptomatic improvement was a decrease from the patient’s baseline GCSI score of at least 50% on 2 consecutive 3-week GCSI assessments during 15 weeks of treatment. RESULTS The primary symptomatic improvement outcome did not differ between 65 patients randomized to nortriptyline vs 65 patients randomized to placebo: 15 (23% 95% CI, 14%-35%) in the nortriptyline group vs 14 (21% 95% CI, 12%-34%) in the placebo group (P = .86). Treatment was stopped more often in the nortriptyline group (19 29% {95% CI, 19%-42%}) than in the placebo group (6 9% {95% CI, 3%-19%}) (P = .007), but numbers of adverse events were not different (27 95% CI, 18-39 vs 28 95% CI, 19-40) (P = .89). CONCLUSIONS AND RELEVANCE Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms. These findings do not support the use of nortriptyline for idiopathic gastroparesis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00765895
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