Has primary care antimicrobial use really been increasing? Comparison of changes in different prescribing measures for a complete geographic population 1995-2014

Objectives To elucidate how population trends in total antimicrobials dispensed in the community translate into individual exposure. Methods Retrospective, population-based observational study of all antimicrobial prescribing in a Scottish region in financial years 1995, 2000 and 2005–14. Analysis of temporal changes in all antimicrobials and specific antimicrobials measured in: WHO DDD per 1000 population; prescriptions per 1000 population; proportion of population with ≥1 prescription; mean number of prescriptions per person receiving any; mean DDD per prescription. Results Antimicrobial DDD increased between 1995 and 2014, from 5651 to 6987 per 1000 population [difference 1336 (95% CI 1309–1363)]. Prescriptions per 1000 fell (from 821 to 667, difference –154, –151 to –157), as did the proportion prescribed any antimicrobial [from 39.3% to 30.8% (–8.5, –8.4 to –8.6)]. Rising mean DDD per prescription, from 6.88 in 1995 to 10.47 in 2014 (3.59, 3.55–3.63), drove rising total DDD. In the under-5s, every measure fell over time (68.2% fall in DDD per 1000; 60.7% fall in prescriptions per 1000). Among 5–64 year olds, prescriptions per 1000 were lowest in 2014 but among older people, despite a reduction since 2010, the 2014 rate was still higher than in 2000. Trends in individual antimicrobials provide some explanation for overall trends. Conclusions Rising antimicrobial volumes up to 2011 were mainly due to rising DDD per prescription. Trends in dispensed drug volumes do not readily translate into information on individual exposure, which is more relevant for adverse consequences including emergence of resistance.PostprintPeer reviewe

The reliability of glomerular filtration rate measured from plasma clearance: a multi-centre study of 1,878 healthy potential renal transplant donors

PURPOSE The objective of the study was to undertake a clinical audit of departmental performance in the measurement of glomerular filtration rate (GFR) using the coefficient of variation (CV) of extracellular fluid volume (ECFV) as the benchmark. ECFV is held within narrow limits in healthy subjects, narrower than GFR, and should therefore have a low CV. METHODS Fifteen departments participated in this retrospective study of healthy renal transplant donors. Data were analysed separately for men (n ranged from 28 to 115 per centre; total = 819) and women (n = 28-146; 1,059). All centres used the slope-intercept method with blood sample numbers ranging from two to five. Subjects did not fast prior to GFR measurement. GFR was scaled to body surface area (BSA) and corrected for the single compartment assumption. GFR scaled to ECFV was calculated as the terminal slope rate constant and corrected for the single compartment assumption. ECFV/BSA was calculated as the ratio of GFR/BSA to GFR/ECFV. RESULTS The departmental CVs of ECFV/BSA and GFR/BSA ranged from 8.3 to 25.8% and 12.8 to 21.9%, respectively, in men, and from 9.6 to 21.1% and 14.8 to 23.7%, respectively, in women. Both CVs correlated strongly between men and women from the same centre, suggesting department-specific systematic errors. GFR/BSA was higher in men in 14 of 15 centres, whereas GFR/ECFV was higher in women in 14 of 15 centres. Both correlated strongly between men and women, suggesting regional variation in GFR. CONCLUSION The CV of ECFV/BSA in normal subjects is a useful indicator of the technical robustness with which GFR is measured and, in this study, indicated a wide variation in departmental performance

Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia

MicroRNA (miRNA)-17-92 cluster (miR-17-92), containing seven individual miRNAs, is frequently amplified and overexpressed in lymphomas and various solid tumors. We have found that it is also frequently amplified and the miRNAs are aberrantly overexpressed in mixed lineage leukemia (MLL)-rearranged acute leukemias. Furthermore, we show that MLL fusions exhibit a much stronger direct binding to the locus of this miRNA cluster than does wild-type MLL; these changes are associated with elevated levels of histone H3 acetylation and H3K4 trimethylation and an up-regulation of these miRNAs. We further observe that forced expression of this miRNA cluster increases proliferation and inhibits apoptosis of human cells. More importantly, we show that this miRNA cluster can significantly increase colony-forming capacity of normal mouse bone marrow progenitor cells alone and, particularly, in cooperation with MLL fusions. Finally, through combinatorial analysis of miRNA and mRNA arrays of mouse bone marrow progenitor cells transfected with this miRNA cluster and/or MLL fusion gene, we identified 363 potential miR-17-92 target genes that exhibited a significant inverse correlation of expression with the miRNAs. Remarkably, these potential target genes are significantly enriched (P < 0.01; >2-fold) in cell differentiation, hematopoiesis, cell cycle, and apoptosis. Taken together, our studies suggest that overexpression of miR-17-92 cluster in MLL-rearranged leukemias is likely attributed to both DNA copy number amplification and direct up-regulation by MLL fusions, and that the miRNAs in this cluster may play an essential role in the development of MLL-associated leukemias through inhibiting cell differentiation and apoptosis, while promoting cell proliferation, by regulating relevant target genes

Management evaluation of metastasis in the brain (MEMBRAIN)—a United Kingdom and Ireland prospective, multicenter observational study

Background: In recent years an increasing number of patients with cerebral metastasis (CM) have been referred to the neuro-oncology multidisciplinary team (NMDT). Our aim was to obtain a national picture of CM referrals to assess referral volume and quality and factors affecting NMDT decision making. Methods: A prospective multicenter cohort study including all adult patients referred to NMDT with 1 or more CM was conducted. Data were collected in neurosurgical units from November 2017 to February 2018. Demographics, primary disease, KPS, imaging, and treatment recommendation were entered into an online database. Results: A total of 1048 patients were analyzed from 24 neurosurgical units. Median age was 65 years (range, 21-93 years) with a median number of 3 referrals (range, 1-17 referrals) per NMDT. The most common primary malignancies were lung (36.5%, n = 383), breast (18.4%, n = 193), and melanoma (12.0%, n = 126). A total of 51.6% (n = 541) of the referrals were for a solitary metastasis and resulted in specialist intervention being offered in 67.5% (n = 365) of cases. A total of 38.2% (n = 186) of patients being referred with multiple CMs were offered specialist treatment. NMDT decision making was associated with number of CMs, age, KPS, primary disease status, and extent of extracranial disease (univariate logistic regression, P &lt; .001) as well as sentinel location and tumor histology (P &lt; .05). A delay in reaching an NMDT decision was identified in 18.6% (n = 195) of cases. Conclusions: This study demonstrates a changing landscape of metastasis management in the United Kingdom and Ireland, including a trend away from adjuvant whole-brain radiotherapy and specialist intervention being offered to a significant proportion of patients with multiple CMs. Poor quality or incomplete referrals cause delay in NMDT decision making