Barts Health NHS Trust

About: Barts Health NHS Trust is a healthcare organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Medicine. The organization has 3483 authors who have published 3807 publications receiving 81829 citations.

Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study.

Abstract: The aim of the RUBY study was to evaluate novel candidate biomarkers to enable prediction of persistence of renal dysfunction as well as further understand potential mechanisms of kidney tissue damage and repair in acute kidney injury (AKI). The RUBY study was a multi-center international prospective observational study to identify biomarkers of the persistence of stage 3 AKI as defined by the KDIGO criteria. Patients in the intensive care unit (ICU) with moderate or severe AKI (KDIGO stage 2 or 3) were enrolled. Patients were to be enrolled within 36 h of meeting KDIGO stage 2 criteria. The primary study endpoint was the development of persistent severe AKI (KDIGO stage 3) lasting for 72 h or more (NCT01868724). 364 patients were enrolled of whom 331 (91%) were available for the primary analysis. One hundred ten (33%) of the analysis cohort met the primary endpoint of persistent stage 3 AKI. Of the biomarkers tested in this study, urinary C–C motif chemokine ligand 14 (CCL14) was the most predictive of persistent stage 3 AKI with an area under the receiver operating characteristic curve (AUC) (95% CI) of 0.83 (0.78–0.87). This AUC was significantly greater than values for other biomarkers associated with AKI including urinary KIM-1, plasma cystatin C, and urinary NGAL, none of which achieved an AUC > 0.75. Elevated urinary CCL14 predicts persistent AKI in a large heterogeneous cohort of critically ill patients with severe AKI. The discovery of CCL14 as a predictor of persistent AKI and thus, renal non-recovery, is novel and could help identify new therapeutic approaches to AKI.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report

Abstract: The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

Both cladribine and alemtuzumab may effect MS via B-cell depletion.

Abstract: OBJECTIVE To understand the efficacy of cladribine (CLAD) treatment in MS through analysis of lymphocyte subsets collected, but not reported, in the pivotal phase III trials of cladribine and alemtuzumab induction therapies. METHODS The regulatory submissions of the CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) (NCT00213135) cladribine and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one (CARE-MS I) (NCT00530348) alemtuzumab trials were obtained from the European Medicine Agency through Freedom of Information requests. Data were extracted and statistically analyzed. RESULTS Either dose of cladribine (3.5 mg/kg; 5.25 mg/kg) tested in CLARITY reduced the annualized relapse rate to 0.16-0.18 over 96 weeks, and both doses were similarly effective in reducing the risk of MRI lesions and disability. Surprisingly, however, T-cell depletion was rather modest. Cladribine 3.5 mg/kg depleted CD4+ cells by 40%-45% and CD8+ cells by 15%-30%, whereas alemtuzumab suppressed CD4+ cells by 70%-95% and CD8+ cells by 47%-55%. However, either dose of cladribine induced 70%-90% CD19+ B-cell depletion, similar to alemtuzumab (90%). CD19+ cells slowly repopulated to 15%-25% of baseline before cladribine redosing. However, alemtuzumab induced hyperrepopulation of CD19+ B cells 6-12 months after infusion, which probably forms the substrate for B-cell autoimmunities associated with alemtuzumab. CONCLUSIONS Cladribine induced only modest depletion of T cells, which may not be consistent with a marked influence on MS, based on previous CD4+ T-cell depletion studies. The therapeutic drug-response relationship with cladribine is more consistent with lasting B-cell depletion and, coupled with the success seen with monoclonal CD20+ depletion, suggests that B-cell suppression could be the major direct mechanism of action.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Abstract: Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.