Steroid use in acute liver failure

Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (\u3e40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH \u3c 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. CONCLUSION: Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell–mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell–mediated inflammatory disease

Development of a risk score for early saphenous vein graft failure: An individual patient data meta-analysis

Objectives: Early saphenous vein graft (SVG) occlusion is typically attributed to technical factors. We aimed at exploring clinical, anatomical, and operative factors associated with the risk of early SVG occlusion (within 12 months postsurgery). Methods: Published literature in MEDLINE was searched for studies reporting the incidence of early SVG occlusion. Individual patient data (IPD) on early SVG occlusion were used from the SAFINOUS-CABG Consortium. A derivation (n = 1492 patients) and validation (n = 372 patients) cohort were used for model training (with 10-fold cross-validation) and external validation respectively. Results: In aggregate data meta-analysis (48 studies, 41,530 SVGs) the pooled estimate for early SVG occlusion was 11%. The developed IPD model for early SVG occlusion, which included clinical, anatomical, and operative characteristics (age, sex, dyslipidemia, diabetes mellitus, smoking, serum creatinine, endoscopic vein harvesting, use of complex grafts, grafted target vessel, and number of SVGs), had good performance in the derivation (c-index = 0.744; 95% confidence interval [CI], 0.701-0.774) and validation cohort (c-index = 0.734; 95% CI, 0.659-0.809). Based on this model. we constructed a simplified 12-variable risk score system (SAFINOUS score) with good performance for early SVG occlusion (c-index = 0.700, 95% CI, 0.684-0.716). Conclusions: From a large international IPD collaboration, we developed a novel risk score to assess the individualized risk for early SVG occlusion. The SAFINOUS risk score could be used to identify patients that are more likely to benefit from aggressive treatment strategies

Extensor tendon release in tennis elbow: results and prognostic factors in 80 elbows

Purpose The objectives of this study were to evaluate the results in the outpatient treatment of recalcitrant lateral epicondylitis with release of the common extensor origin according to Hohmann and to determine any prognostic factors. Methods Eighty tennis elbows in 77 patients with a characteristic history of activity-related pain at the lateral epicondyle interfering with the activities of daily living refractory to conservative care for at least 6 months and a confirmatory physical examination were included. Clinical outcome was evaluated using the QuickDASH score system. Data were collected before the operation and at the medians of 18 months (range 6–36 months; short term) and 4 years (range 3–6 years; medium term) postoperatively. Results The mean QuickDASH was improved both at the short- and the medium-term follow-ups and did not change significantly between the follow-ups. At the final followup, the QuickDASH was improved in 78 out of 80 elbows and 81% was rated as excellent or good (QuickDASH\40 points). We found a weak correlation between residual symptoms (a high QuickDASH score) at the final follow-up and high level of baseline symptoms (r = 0.388), acute occurrence of symptoms (r = 0.362), long duration of symptoms (r = 0.276), female gender (r = 0.269) and young age (r = 0.203), whereas occurrence in dominant arm, a work-related cause or strenuous work did not correlate significantly with the outcome. Conclusion Open lateral extensor release performed as outpatient surgery results in improved clinical outcome at both short- and medium-term follow-ups with few complications. High baseline disability, sudden occurrence of symptoms, long duration of symptoms, female gender and young age were found to be weak predictors of poor outcome

Rapid intrapartum test for maternal group B streptococcal colonisation and its effect on antibiotic use in labouring women with risk factors for early-onset neonatal infection (GBS2): cluster randomised trial with nested test accuracy study

Background: Mother-to-baby transmission of group B Streptococcus (GBS) is the main cause of early-onset infection. We evaluated whether, in women with clinical risk factors for early neonatal infection, the use of point-of-care rapid intrapartum test to detect maternal GBS colonisation reduces maternal antibiotic exposure compared with usual care, where antibiotics are administered due to those risk factors. We assessed the accuracy of the rapid test in diagnosing maternal GBS colonisation, against the reference standard of selective enrichment culture. Methods: We undertook a parallel-group cluster randomised trial, with nested test accuracy study and microbiological sub-study. UK maternity units were randomised to a strategy of rapid test (GeneXpert GBS system, Cepheid) or usual care. Within units assigned to rapid testing, vaginal-rectal swabs were taken from women with risk factors for vertical GBS transmission in established term labour. The trial primary outcome was the proportion of women receiving intrapartum antibiotics to prevent neonatal early-onset GBS infection. The accuracy of the rapid test was compared against the standard of selective enrichment culture in diagnosing maternal GBS colonisation. Antibiotic resistance profiles were determined in paired maternal and infant samples. Results: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units; 906 mothers (951 babies) were in usual care units. There was no evidence of a difference in the rates of intrapartum antibiotic prophylaxis (relative risk 1.16, 95% CI 0.83 to 1.64) between the rapid test (41%, 297/716) and usual care (36%, 328/906) units. No serious adverse events were reported. The sensitivity and specificity measures of the rapid test were 86% (95% CI 81 to 91%) and 89% (95% CI 85 to 92%), respectively. Babies born to mothers who carried antibiotic-resistant Escherichia coli were more likely to be colonised with antibiotic-resistant strains than those born to mothers with antibiotic-susceptible E. coli. Conclusion: The use of intrapartum rapid test to diagnose maternal GBS colonisation did not reduce the rates of antibiotics administered for preventing neonatal early-onset GBS infection than usual care, although with considerable uncertainty. The accuracy of the rapid test is within acceptable limits. Trial registration: ISRCTN74746075. Prospectively registered on 16 April 2015

Infant mortality and isotopic complexity: new approaches to stress, maternal health, and weaning

Objectives: Studies of the carbon and nitrogen stable isotope ratios (δ13C and δ15N) of modern tissues with a fast turnover, such as hair and fingernails, have established the relationship between these values in mothers and their infants during breastfeeding and weaning. Using collagen from high-resolution dentine sections of teeth, which form in the perinatal period we investigate the relationship between diet and physiology in this pivotal stage of life. Materials and Methods: Childhood dentine collagen δ13C and δ15N profiles were produced from horizontal sections of permanent and deciduous teeth following the direction of development. These were from two 19th-century sites (n = 24) and a small number (n = 5) of prehistoric samples from Great Britain and Ireland. Results: These high-resolution data exhibit marked differences between those who survived childhood and those who did not, the former varying little and the latter fluctuating widely. Discussion: Breastfeeding and weaning behavior have a significant impact on the morbidity and mortality of infants and the adults they become. In the absence of documentary evidence, archaeological studies of bone collagen of adults and juveniles have been used to infer the prevalence and duration of breastfeeding. These interpretations rely on certain assumptions about the relationship between isotope ratios in the bone collagen of the adult females and the infants who have died. The data from this study suggest a more complex situation than previously proposed and the potential for a new approach to the study of maternal and infant health in past populations