Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C9 and HLA-B Genotype and Phenytoin Dosing

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large inter-patient variability partly due to genetic variations in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: www.pharmgkb.org)

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing: 2015 update

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org)

Measurement of synovial tissue volume in knee osteoarthritis using a semiautomated MRI-based quantitative approach

© 2019 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. Purpose: Synovitis is common in knee osteoarthritis and is associated with both knee pain and progression of disease. Semiautomated methods have been developed for quantitative assessment of structure in knee osteoarthritis. Our aims were to apply a novel semiautomated assessment method using 3D active appearance modeling for the quantification of synovial tissue volume (STV) and to compare its performance with conventional manual segmentation. Methods: Thirty-two sagittal T 1 -weighted fat-suppressed contrast-enhanced MRIs were assessed for STV by a single observer using 1) manual segmentation and 2) a semiautomated approach. We compared the STV analysis using the semiautomated and manual segmentation methods, including the time taken to complete the assessments. We also examined the reliability of STV assessment using the semiautomated method in a subset of 12 patients who had participated in a clinical trial of vitamin D therapy in knee osteoarthritis. Results: There was no significant difference in STV using the semiautomated quantitative method compared to manual segmentation, mean difference = 207.2 mm 3 (95% confidence interval −895.2 to 1309.7). The semiautomated method was significantly quicker than manual segmentation (18 vs. 71 min). For the semiautomated method, intraobserver agreement was excellent (intraclass correlation coefficient (3,1) = 0.99) and interobserver agreement was very good (intraclass correlation coefficient (3,1) = 0.83). Conclusion: We describe the application of a semiautomated method that is accurate, reliable, and quicker than manual segmentation for assessment of STV. The method may help increase efficiency of image assessment in large imaging studies and may also assist investigation of treatment efficacy in knee osteoarthritis

Quantitative imaging of concentrated suspensions under flow

We review recent advances in imaging the flow of concentrated suspensions, focussing on the use of confocal microscopy to obtain time-resolved information on the single-particle level in these systems. After motivating the need for quantitative (confocal) imaging in suspension rheology, we briefly describe the particles, sample environments, microscopy tools and analysis algorithms needed to perform this kind of experiments. The second part of the review focusses on microscopic aspects of the flow of concentrated model hard-sphere-like suspensions, and the relation to non-linear rheological phenomena such as yielding, shear localization, wall slip and shear-induced ordering. Both Brownian and non-Brownian systems will be described. We show how quantitative imaging can improve our understanding of the connection between microscopic dynamics and bulk flow.Comment: Review on imaging hard-sphere suspensions, incl summary of methodology. Submitted for special volume 'High Solid Dispersions' ed. M. Cloitre, Vol. xx of 'Advances and Polymer Science' (Springer, Berlin, 2009); 22 pages, 16 fig

Task shifting to non-physician clinicians for integrated management of hypertension and diabetes in rural Cameroon: a programme assessment at two years

<p>Abstract</p> <p>Background</p> <p>The burden of non-communicable chronic diseases, such as hypertension and diabetes, increases in sub-Saharan Africa. However, the majority of the rural population does still not have access to adequate care. The objective of this study is to examine the effectiveness of integrating care for hypertension and type 2 diabetes by task shifting to non-physician clinician (NPC) facilities in eight rural health districts in Cameroon.</p> <p>Methods</p> <p>Of the 75 NPC facilities in the area, 69 (87%) received basic equipment and training in hypertension and diabetes care. Effectiveness was assessed after two years on status of equipment, knowledge among trained NPCs, number of newly detected patients, retention of patients under care, treatment cost to patients and changes in blood pressure (BP) and fasting plasma glucose (FPG) among treated patients.</p> <p>Results</p> <p>Two years into the programme, of 54 facilities (78%) available for re-assessment, all possessed a functional sphygmomanometer and stethoscope (65% at baseline); 96% stocked antihypertensive drugs (27% at baseline); 70% possessed a functional glucose meter and 72% stocked oral anti-diabetics (15% and 12% at baseline). NPCs' performance on multiple-choice questions of the knowledge-test was significantly improved. During a period of two years, trained NPCs initiated treatment for 796 patients with hypertension and/or diabetes. The retention of treated patients at one year was 18.1%. Hypertensive and diabetic patients paid a median monthly amount of 1.4 and 0.7 Euro respectively for their medication. Among hypertensive patients with ≥ 2 documented visits (n = 493), systolic BP decreased by 22.8 mmHg (95% CI: -20.6 to -24.9; p < 0.0001) and diastolic BP by 12.4 mmHg (-10.9 to -13.9; p < 0.0001). Among diabetic patients (n = 79) FPG decreased by 3.4 mmol/l (-2.3 to -4.5; p < 0.001).</p> <p>Conclusions</p> <p>The integration of hypertension and diabetes into primary health care of NPC facilities in rural Cameroon was feasible in terms of equipment and training, accessible in terms of treatment cost and showed promising BP- and FPG-trends. However, low case-detection rates per NPC and a very high attrition among patients enrolled into care, limited the effectiveness of the programme.</p

Analysis of two methods of isometric muscle contractions during the anti-G straining maneuver

This study investigated the difference in Mean Arterial Pressure (MAP) and Cardiac Output (CO) between two methods of isometric muscle contractions during the Anti-G Straining Maneuver (AGSM). 12 subjects (ages 18 to 38 yrs, height 176.8 +/- 7.4 cm, body mass 78.8 +/- 15.6 kg, percent body fat 14.3 +/- 6.6%) participated in the study. The study was a one-way within-subject design with test conditions counterbalanced. Two methods of isometric muscle contractions lasting 30 seconds each were assessed; an isometric push contraction and an isometric muscle tensing contraction. The dependent parameters were MAP and CO. The average MAP during the push contraction was 123 mmHg, SD +/- 11 and for tense was 118 mmHg, SD +/- 8. CO was 7.6 L/min, SD +/- 1.6 for push and 7.9 L/min, SD +/- 2.0 for tense method. Dependent t-tests revealed t(11) = 1.517, p = 0.157 for MAP and t(11) = 0.875, p = 0.400 for CO. This study demonstrated that the two methods of isometric muscle contractions were not statistically different with regards to MAP and CO. Therefore, both forms of isometric contractions may be potentially useful when performing the muscle contraction portion of the AGSM

Proteomic profiling of Burkholderia cenocepacia clonal isolates with different virulence potential retrieved from a cystic fibrosis patient during chronic lung infection

Respiratory infections with Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) are associated with a worse prognosis and increased risk of death. In this work, we assessed the virulence potential of three B. cenocepacia clonal isolates obtained from a CF patient between the onset of infection (isolate IST439) and before death with cepacia syndrome 3.5 years later (isolate IST4113 followed by IST4134), based on their ability to invade epithelial cells and compromise epithelial monolayer integrity. The two clonal isolates retrieved during late-stage disease were significantly more virulent than IST439. Proteomic profiling by 2-D DIGE of the last isolate recovered before the patient's death, IST4134, and clonal isolate IST439, was performed and compared with a prior analysis of IST4113 vs. IST439. The cytoplasmic and membrane-associated enriched fractions were examined and 52 proteins were found to be similarly altered in the two last isolates compared with IST439. These proteins are involved in metabolic functions, nucleotide synthesis, translation and protein folding, cell envelope biogenesis and iron homeostasis. Results are suggestive of the important role played by metabolic reprogramming in the virulence potential and persistence of B. cenocepacia, in particular regarding bacterial adaptation to microaerophilic conditions. Also, the content of the virulence determinant AidA was higher in the last 2 isolates. Significant levels of siderophores were found to be secreted by the three clonal isolates in an iron-depleted environment, but the two late isolates were more tolerant to low iron concentrations than IST439, consistent with the relative abundance of proteins involved in iron uptake.This work was supported by FEDER and FCT – Fundação para a Ciência e a Tecnologia (contract PEst-OE/EQB/LA0023/2011_ research line: Systems and Synthetic Biology; PhD grant to A.M. – SFRH/BD/37012/2007, and PD grants to S.S. – SFRH/BPD/75483/2010 and C.C. – SFRH/BPD/ 81220/2011. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio