Background Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 ( CYP) 2D6 gene, or to identify the promoter (TA) 7 TAA repeat polymorphism UDP glucuronosyltransferase ( UGT) 1A1 *28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. Methods A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. Results Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28 . Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. Conclusions PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine. Electronic supplementary material The online version of this article (10.1186/s12920-019-0527-2) contains supplementary material, which is available to authorized users.

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Background Blunt abdominal solid organ injury is common and is often managed nonoperatively. Clinicians must balance risk of both hemorrhage and thrombosis. The optimal timing of pharmacologic venous thromboembolism prophylaxis (VTEp) initiation in this population is unclear. The objective was to evaluate early (< 48 h) compared to late initiation of VTEp in adult trauma patients with blunt abdominal solid organ injury managed nonoperatively. Methods Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched from inception to March 2021. Studies comparing timeframes of VTEp initiation were considered. The primary outcome was failure of nonoperative management (NOM) after VTEp initiation. Secondary outcomes included risk of transfusion, other bleeding complications, risk of deep vein thrombosis (DVT) and pulmonary embolism, and mortality. Results Ten cohort studies met inclusion criteria, with a total of 4642 patients. Meta-analysis revealed a statistically significant increase in the risk of failure of NOM among patients receiving early VTEp (OR 1.76, 95% CI 1.01–3.05, p = 0.05). There was no significant difference in risk of transfusion. Odds of DVT were significantly lower in the early group (OR 0.36, 95% CI 0.22–0.59, p < 0.0001). There was no difference in mortality (OR 1.50, 95% CI 0.82–2.75, p = 0.19). All studies were at serious risk of bias due to confounding. Conclusions Initiation of VTEp earlier than 48 h following hospitalization is associated with an increased risk of failure of NOM but a decreased risk of DVT. Absolute failure rates of NOM are low. Initiation of VTEp at 48 h may balance the risks of bleeding and VTE.

Objective: To compare blood pressure readings obtained with two commonly used oscillometric monitors: Omron HEM 711 AC (OM) and Welch-Allyn 52000 series NIBP/ oximeter (WA) with mercury sphygmomanometers (Merc) in subjects with atrial fibrillation. Methods: We recruited 51 hemodynamically stable subjects with atrial fibrillation. Fifty four subjects in normal sinus rhythm served as controls. Supine blood pressure readings in each arm were recorded simultaneously using one monitor and Merc. The second monitor then replaced the first and readings were repeated. Merc was then switched to the opposite arm, and both monitors retested. Apical heart rates were ascertained with a stethoscope. We used the averaged, same arm Merc readings as "gold standard". Results: Automated blood pressure readings were obtained in all control subjects and in all but three of those with atrial fibrillation. Both monitors, and operators, noted a difference between apical and radial/brachial pulse rates: apical-recorded: Merc 6.1±15.0; OM 5.5±13.7; WA 10.0±21.2 beats per minute. Both monitors were accurate in controls: over 90% of readings were within 10 mmHg of averaged Merc, and both achieved European Hypertension Society standards. In subjects with atrial fibrillation, about one quarter of all oscillometric readings differed from Merc by more than 10 mmHg. Both falsely high and falsely low readings occurred, some up to 30 mmHg. There was no relation between accuracy and heart rate. Conclusions: Single blood pressure readings, taken with oscillometric monitors in subjects with atrial fibrillation differ, often markedly, from those taken manually. Health care professionals should record multiple readings manually, using validated instruments when making therapeutic decisions.