Elgaard Hoyle (toadsand95)

OBJECTIVES The extent of hereditary haemorrhagic telangiectasia (HHT) and pulmonary arteriovenous malformations (PAVM) as a risk factor for brain abscess is unknown. METHODS Nationwide and population-based registries were used to identify persons with first-time hospitalization for brain abscess (index date) and population controls matched by age, sex, and residence (110). Accounting for competing risks, cumulative incidence curves of new diagnosis of HHT/PAVM after brain abscess were constructed. Next, Cox regression was used for computation of cause-specific hazard rate ratios (HRRs) adjusted for severe liver disease and congenital heart disease as potential confounders. RESULTS HHT/PAVM was prevalent before the index date in 2/1,384 (0.1% [95% CI 0.02-0.52]) brain abscess patients and 6/13,838 (0.04% [95% CI 0.02-0.09]) matched population controls. After the index date, a new diagnosis of hereditary haemorrhagic telangiectasia or pulmonary arteriovenous malformations was made in 15/1,384 brain abscess patients (range 0 days to 17 years) compared with 7/13,812 population controls yielding an adjusted hazard rate ratio of 31.4 (95% CI 9.95-98.9). selleck chemicals Cumulative incidence was 1.5% for brain abscess patients and 0.1% for population controls. CONCLUSIONS HHT/PAVM should be considered in patients with cryptogenic brain abscess, although absolute risk is low. BACKGROUND Therapeutic drug monitoring (TDM) is a tool to personalize and optimise dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM. OBJECTIVES We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM. SOURCES The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM. CONTENT This review focuses on key aspects of antimicrobial TDM study design describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design. IMPLICATIONS This is an overview of different aspects relevant for the conduct of a TDM study. We believe that this paper will help researchers and clinicians to design and conduct high quality TDM studies. Stratification of patients for targeted and immune-based therapies requires extensive genomic profiling that enables sensitive detection of clinically relevant variants and interrogation of biomarkers such as tumor mutational burden (TMB) and microsatellite instability (MSI). We evaluated the detection of single and multiple nucleotide variants, copy number variants, MSI and TMB using a commercially available next-generation sequencing panel containing 523 cancer-related genes (1.94 Mb). Analysis of formalin-fixed, paraffin-embedded tissue sections and cytological material from 45 tumor samples showed that all previously known MSI-positive samples (n=7), amplifications (n=9), and pathogenic variants (n=59) could be detected. TMB and MSI scores showed high intra- and interlaboratory reproducibility (8 samples tested in 11 laboratories). For reliable TMB analysis, 20 ng DNA was shown to be sufficient, even for relatively poor-quality samples. A minimum of 20% neoplastic cells was required to minimize variations in TMB values induced by chromosomal instability or tumor heterogeneity. Subsequent analysis of 58 consecutive lung cancer samples in a diagnostic setting was successful and revealed sufficient somatic mutations to generate mutational signatures in 14 cases. In conclusion, the 523-gene assay can be applied for evaluat