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9% vs. 50.0% for A(H3N2) patients and 77.8% for B patients; p less then 0.01). Overall, mortality at 90 days post-admission was 33.3% (15/45), and there was no significant difference between influenza type and subtype. The need for extracorporeal membrane oxygenation was more frequent for A(H1N1)pdm2009 (20/28, 71.4%) and B patients (7/9, 77.8%) as compared to the A(H3N2) subtype (1/8, 12.5%; p less then 0.01). A(H1N1)pdm09-ARDS patients were associated with fewer ventilation-free days at day 28 (median [IQR] 0[0-8] day) as compared with other influenza-ARDS patients (15 [0-25] days, p less then 0.05). CONCLUSIONS In a population of influenza-induced ARDS, A(H1N1)pdm09 was associated with fewer bacterial co-infections but poorer respiratory outcomes. These data underline the major role of A(H1N1)pdm09 subtype on influenza disease severity. 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). 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. see more In conclusion, the 523-gene assay can be applied for evaluation of multiple DNA-based biomarkers relevant for treatment selection. Spinal muscular atrophy (SMA) is a relatively common, life-shortening, autosomal recessive neuromuscular disease. The carrier frequency of SMA ranges from approximately 0.98% to 2.02% depending on ethnicity. The American College of Medical Genetics has therefore recommended population screening for SMA carrier status, regardless of race or ethnicity. We carried out the largest-scale carrier screening for SMA carriers in mainland China. Carrier screening was offered to 36 470 pregnant women between July 2017 and June 2019, of whom 13 069 women accepted the screening program (35.83%, 95% CI 35.34%-36.33%). We detected copy numbers of exons 7 and 8 in the SMN1 gene by quantitative real-time polymerase chain reaction and confirmed the results by multiplex ligation-dependent probe amplification. A total of 231 women were identified as carriers (1.77%, 95% CI, 1.56%-2.01%) indicating a carrier prevalence of about 156 in the population. After detailed genetic counseling, 207 paternal partners were recalled and tested. Both partners were carriers in 10 couples, of whom prenatal diagnosis was implemented in seven, and one fetus was diagnosed with SMA. link2 Carrier screening could provide couples with informed reproductive choices. Our workflow and experience of carrier screening may facilitate the popularization of SMA carrier screening in mainland China. Liquid biopsies have emerged as a useful addition to tissue biopsies in the field of molecular pathology. Previous literature has shown lower laboratory performances when a new technique or method for variant analysis is introduced. The aim of this study was to evaluate the differences in variant analysis between tissue and plasma samples after its introduction as a new sample type for molecular analysis. Data from a pilot external quality assessment scheme for the detection of molecular variants in plasma samples and external quality assessment schemes on tissue samples were collected. Subsequently, laboratory performances and error rates on sample level were compared between matrices for variants present in both scheme types. Results show lower overall performances (65.6%, n=276 compared to 89.2%, n=1,607) and higher error rates (21.0% to 43.5%, n=138, compared to 8.7% to 16.7%, n=234 to 689) for the detection of variants in plasma compared to tissue. In the plasma samples, performance decreased for variants with an allele frequency of 1% (56.5%, n=138) when compared to 5% (74.6%, n=138). Our analysis confirms that the implementation of new methods for detecting circulating cell-free tumor DNA in cell-free plasma is associated with poor performance. link3 It is important to apply optimal detection methods as well as to extensively validate new methods for cell-free tumor DNA testing before treatment decisions are made. Circulating tumor DNA (ctDNA) measurements can be used to estimate tumor burden, but avoiding false-positives is a challenge. We evaluated digital next-generation sequencing (NGS) as a ctDNA detection method. Plasma KRAS and GNAS hotspot mutation levels were measured in 140 subjects including 67 with pancreatic ductal adenocarcinoma, and 73 healthy and disease controls. To limit chemical modifications of DNA that yield false-positive mutation calls, plasma DNA was enzymatically pre-treated, after which DNA was aliquoted for digital detection of mutations (up to 384 aliquots/sample) by PCR and NGS. A digital NGS score of two standard deviations above the mean in controls was considered positive. 37% of patients with pancreatic cancer, including 31% of patients with Stage I/II disease had positive KRAS codon 12 ctDNA scores; only one patient had a positive GNAS mutation score. Two disease control patients had positive ctDNA scores. Low normal-range digital NGS scores at mutation hot-spots were found at similar levels in healthy and disease controls, usually at sites of cytosine deamination, and were likely the result of chemical modification of plasma DNA and NGS error, rather than true mutations. Digital NGS detects mutated ctDNA in patients with pancreatic cancer with similar yield to other methods. The detection of low-level, true-positive ctDNA is limited by frequent low-level detection of false-positive mutation cells in plasma DNA from controls. Polyglutamine spinocerebellar ataxias (SCAs) constitute a group of autosomal dominantly inherited neurodegenerative disorders with considerable phenotypic overlap. A definitive diagnosis relies on the detection of a mutation in each associated locus, comprising the abnormal expansion of the trinucleotide CAG in coding exons. The assessment of single nucleotide polymorphisms (SNPs) associated with the CAG expansion in the context of SCAs is also relevant for the improvement of molecular diagnosis and for the generation of novel therapeutic strategies. Here we focused on Machado-Joseph disease (MJD)/SCA3, aiming to develop a protocol for the accurate determination of the CAG length in exon 10 of the human ATXN3 gene and to characterize flanking polymorphisms. A single pair of primers was designed and validated, and two complementary PCR-based methods were established. In method I, PCR amplicons were cloned and sequenced, allowing the assessment of three SNPs in the vicinity of the CAG repeat (C987GG/G987GG, TAA1118/TAC1118 and C1178/A1178), which can constitute potential targets for personalized gene-based therapies. Method II combines PCR, capillary electrophoresis and a size correction formula, enabling a time and cost-effective determination of the number of CAGs. The established protocol paves the way to overcome technical difficulties related to the molecular characterization of the CAG motif and intragenic polymorphisms in the context of MJD/SCA3 and may prove its utility when applied to other polyglutamine SCAs. OBJECTIVES This study aimed to evaluate whether tenofovir prophylaxis for mothers with high viral loads in late pregnancy is a cost-effective way to prevent mother-to-child HBV transmission in China. METHODS A decision tree-Markov model was constructed for a cohort of infants born to HBV surface antigen-positive mothers in China, 2016. The expected cost and effectiveness were compared between the current active-passive immunoprophylaxis strategy and the tenofovir prophylaxis strategy and the incremental cost-effectiveness ratio was calculated. One-way and multi-way probabilistic sensitivity analyses were performed. RESULTS For 100,000 babies born to mothers positive for hepatitis B surface antigen, tenofovir prophylaxis strategy would prevent 2,213 perinatal HBV infections and gain 931 quality-adjusted life years, compared with the current active-passive immunoprophylaxis strategy. The incremental cost-effectiveness ratio was ￥59,973 ($9,087) per QALY gained. This result was robust over a wide range of assumptions.