Role of the N-acetylation polymorphism in solithromycin metabolism.

Pharmacogenomics. 2017 Jun;18(8):765-772

Authors: Hein DW, Doll MA

Abstract
AIM: Solithromycin is a new macrolide antibiotic for the potential treatment of bacterial pneumonia.
MATERIALS & METHODS: Solithromycin N-acetylation by human NAT1 and NAT2 was investigated following recombinant expression in yeast and in cryopreserved human hepatocytes from rapid, intermediate and slow acetylators.
RESULTS: Solithromycin exhibited over twofold higher affinity for recombinant human NAT2 than NAT1. Apparent maximum velocities for the N-acetylation of solithromycin catalyzed by the NAT2 allozyme associated with rapid acetylators were significantly (p < 0.01) higher than by the NAT2 allozymes associated with slow acetylators. Robust gene dose responses (rapid>intermediate>slow acetylators) were exhibited in cryopreserved human hepatocytes in situ following incubation with 100 μM solithromycin.
CONCLUSION: Solithromycin is N-acetylated by human NAT1 and NAT2 and the role of the NAT2 acetylation polymorphism on solithromycin metabolism may be concentration dependent.

PMID: 28625123 [PubMed - in process]

Identification of Potential Plasma Biomarkers for Nonalcoholic Fatty Liver Disease by Integrating Transcriptomics and Proteomics in Laying Hens.

J Nutr. 2017 Mar;147(3):293-303

Authors: Tsai MT, Chen YJ, Chen CY, Tsai MH, Han CL, Chen YJ, Mersmann HJ, Ding ST

Abstract
Background: Prevalent worldwide obesity is associated with increased incidence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. The identification of noninvasive biomarkers for NAFLD is of recent interest. Because primary de novo lipogenesis occurs in chicken liver as in human liver, adult chickens with age-associated steatosis resembling human NAFLD is an appealing animal model.Objective: The objective of this study was to screen potential biomarkers in the chicken model for NAFLD by transcriptomic and proteomic analysis.Methods: Hy-Line W-36 laying hens were fed standard feed from 25 to 45 wk of age to induce fatty liver. They were killed every 4 wk, and liver and plasma were collected at each time point to assess fatty liver development and for transcriptomic and proteomic analysis. Next, selected biomarkers were confirmed in additional experiments by providing supplements of the hepatoprotective nutrients betaine [300, 600, or 900 parts per million (ppm) in vivo; 2 mM in vitro] or docosahexaenoic acid (DHA; 1% in vivo; 100 μM in vitro) to 30-wk-old Hy-Line W-36 laying hens for 4 mo and to Hy-Line W-36 chicken primary hepatocytes with oleic acid-induced steatosis. Liver or hepatocyte lipid contents and the expression of biomarkers were then examined.Results: Plasma acetoacetyl-CoA synthetase (AACS), dipeptidyl-peptidase 4 (DPP4), glutamine synthetase (GLUL), and glutathione S-transferase (GST) concentrations are well-established biomarkers for NAFLD. Selected biomarkers had significant positive associations with hepatic lipid deposition (P < 0.001). Betaine (900 ppm in vivo; 2 mM in vitro) and DHA (1% in vivo; 100 μM in vitro) supplementation both resulted in lower steatosis accompanied by the reduced expression of selected biomarkers in vivo and in vitro (P < 0.05).Conclusion: This study used adult laying hens to identify biomarkers for NAFLD and indicated that AACS, DPP4, GLUL, and GST could be considered to be potential diagnostic indicators for NAFLD in the future.

PMID: 28077733 [PubMed - indexed for MEDLINE]

Impact of VKORC1 gene polymorphisms on warfarin maintenance dosage: A novel systematic review and meta-analysis of 53 studies.

Int J Clin Pharmacol Ther. 2017 Apr;55(4):304-321

Authors: Tang W, Shi QP, Ding F, Yu ML, Hua J, Wang YX

Abstract
OBJECTIVE: To analyze the correlation between <i>VKORC1</i> gene polymorphisms and warfarin maintenance dosage, as well as the correlation of dosage of warfarin with age and ethnicity.
METHODS: We retrieved related studies published between January 2000 and March 2016 from PubMed, Embase, the Cochrane Library, Web of Science, VIP, CNKI, and Wan Fang data. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data and crosscheck data. Then, RevMan5.3 software was used to perform a meta-analysis.
RESULTS: 53 studies were included in the meta-analysis. The most prevalent genotypes were -1639 AA, 1173 TT, and 3730 GG in both Asian and Caucasians, but the distribution frequencies of all three were higher in Asians than in Caucasians. The meta-analysis showed that compared with homozygous <i>VKORC1</i>-1639 AA carriers, carriers of type GA, GG, and G (GA + GG) required 45% (95% confidence interval (CI) 42 - 49), 77% (95% CI 70 - 84), and 51% (95% CI 47 - 55) higher warfarin doses, respectively. Carriers of type CC, TC, and C (CC + TC) required 83% (95% CI 73 - 92), 26% (95% CI 23 - 29), and 53% (95% CI 44 - 62) higher warfarin doses, respectively, compared to homozygous <i>VKORC1</i> 1173 TT carriers. Carriers of type AA, GA, and A (AA + GA) required 40% (95% CI 29 - 51), 25% (95% CI 17 - 33), and 33% (95% CI 21 - 45) higher warfarin doses, respectively, compared to carriers of the homozygous <i>VKORC1</i> 3730 GG polymorphism (all p < 0.05). Subgroup analysis showed that Asian patients aged ≤ 60 years carrying 1173 CC, TC, and C genotypes required 28%, 39%, and 22% higher warfarin doses, respectively, compared with patients aged > 60 years. Caucasian patients aged > 60 years carrying -1639 GA, GG and G genotypes needed 24%, 39%, and 37% lower warfarin doses, respectively, compared with patients aged ≤ 60 years. These differences were statistically significant (p < 0.05).
CONCLUSIONS: Our study showed that the relationship between <italic>VKORC1</italic> gene polymorphisms and warfarin maintenance dose differs between individuals, and that individuals with different ages and ethnicities require different doses of warfarin. Caucasians carriers of genotype -1639 GG, G and 1173 CC, TC, C required a higher mean daily warfarin doses compared with Asian patients. Therefore, in order to achieve optimal treatment and lowest risk, <i>VKORC1</i> gene polymorphism detection is suggested.
.

PMID: 28025970 [PubMed - indexed for MEDLINE]

Combination antimicrobial susceptibility testing for acute exacerbations in chronic infection of Pseudomonas aeruginosa in cystic fibrosis.

Cochrane Database Syst Rev. 2017 Jun 19;6:CD006961

Authors: Waters V, Ratjen F

Abstract
BACKGROUND: Antibiotic therapy for acute pulmonary exacerbations in people with cystic fibrosis is usually chosen based on the results of antimicrobial susceptibility testing of individual drugs. Combination antimicrobial susceptibility testing assesses the efficacy of drug combinations including two or three antibiotics in vitro and can often demonstrate antimicrobial efficacy against bacterial isolates even when individual antibiotics have little or no effect. Therefore, choosing antibiotics based on combination antimicrobial susceptibility testing could potentially improve response to treatment in people with cystic fibrosis with acute exacerbations. This is an updated version of a previously published review.
OBJECTIVES: To compare antibiotic therapy based on conventional antimicrobial susceptibility testing to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis and chronic infection with Pseudomonas aeruginosa.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 19 December 2016.We also searched ongoing trials registries. Date of latest search: 08 March 2017.
SELECTION CRITERIA: Randomised and quasi-randomised controlled studies of antibiotic therapy based on conventional antimicrobial susceptibility testing compared to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in cystic fibrosis due to chronic infection with Pseudomonas aeruginosa.
DATA COLLECTION AND ANALYSIS: Both authors independently selected studies, assessed their quality and extracted data from eligible studies. Additionally, the authors contacted the study investigators to obtain further information.
MAIN RESULTS: The search identified one multicentre study eligible for inclusion in the review. This study prospectively assessed whether the use of multiple combination bactericidal antibiotic testing improved clinical outcomes in participants with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria. A total of 132 participants were randomised in the study. The study investigators provided data specific to the 82 participants who were only infected with Pseudomonas aeruginosa for their primary outcome of time until next pulmonary exacerbation. For participants specifically infected with only Pseudomonas aeruginosa, the hazard ratio of a subsequent exacerbation was 0.82, favouring the control group (95% confidence interval 0.44 to 1.51) (P = 0.52). No further data for any of this review's outcomes specific to participants infected with Pseudomonas aeruginosa were available. The risk of bias for the included study was deemed to be low. The quality of the evidence was moderate for the only outcome providing data solely for individuals with infection due to Pseudomonas aeruginosa. For other outcomes, we were unable to judge the quality of the evidence as no data were available for the relevant subset of participants.
AUTHORS' CONCLUSIONS: The current evidence, limited to one study, shows that there is insufficient evidence to determine effect of choosing antibiotics based on combination antimicrobial susceptibility testing compared to choosing antibiotics based on conventional antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis with chronic Pseudomonas aeruginosa infection. A large international and multicentre study is needed to further investigate this issue.The only study included in the review was published in 2005, and we have not identified any further relevant studies up to March 2017. We therefore do not plan to update this review until new studies are published.

PMID: 28628280 [PubMed - as supplied by publisher]

[Excess weight in patients with cystic fibrosis: is it always beneficial?]

Nutr Hosp. 2017 Jun 05;34(3):578-583

Authors: González Jiménez D, Muñoz-Codoceo R, Garriga-García M, Molina-Arias M, Álvarez-Beltrán M, García-Romero R, Martínez-Costa C, Meavilla-Olivas SM, Peña-Quintana LR, Gallego Gutiérrez S, Marugán de Miguelsanz JM, Suárez Cortina L, Castejón Ponce EN, Leis Trabazo R, Martín Cruz F, Díaz Martín JJ, Bousoño García C

Abstract
INTRODUCTION: The primary objective of this study was to find out the prevalence of overweight and obese status, as well as their association to pulmonary function, total cholesterol and vitamin D in patients with cystic fibrosis (CF).
MATERIALS AND METHODS: This is a multicenter descriptive and cross-sectional study. Twelve Spanish hospitals participated. 451 patients with CF were included. Adults were classified according to body mass index (BMI) and children were classified according to BMI percentiles (WHO tables). Pearson's correlation, Anova, Student's t-test and multiple linear regression were conducted.
RESULTS: Mean age was 12.3 (range 4-57) years old, 51% were male and 18% had pancreatic sufficiency. Participants were classified in five nutritional status categories: 12% were malnourished; 57%, at nutritional risk; 24%, normally nourished; 6%, overweight; and 1%, obese. Pulmonary function in overweight or obese patients (91 ± 19%) was better than in malnourished patients (77 ± 24%) (p = 0.017). However, no difference was observed between those at nutritional risk (86 ± 19%) or normally nourished (90 ± 22%) groups. Overweight and obese patients had higher levels of total cholesterol (p = 0.0049), a greater proportion of hypercholesterolemia (p = 0.001), as well as lower levels of 25 OH vitamin D (p = 0.058).
CONCLUSIONS: Prevalence of overweight and obese was 6 and 1%. Excess weight status does not offer any benefit in pulmonary function in comparison to normally nourished patients.

PMID: 28627192 [PubMed - in process]

Continuous glucose monitoring in a cystic fibrosis patient to predict pulmonary exacerbation?

J Cyst Fibros. 2017 Jun 15;:

Authors: Inman TB, Proudfoot JA, Lim M, Demeterco-Berggren C

Abstract
Patients with cystic fibrosis (CF) experience a significant decline in pulmonary status before the diagnosis of cystic fibrosis related diabetes (CFRD). We hypothesized that hyperglycemia may be a factor in the decline of pulmonary function and increased frequency of pulmonary exacerbations. Long term continuous glucose monitoring (CGM) has not been reported in patients with CF and impaired glucose tolerance. We performed CGM for three months in a 17year old male with F508del and F553X CF mutations, baseline forced expiratory volume in 1s (FEV1) of 92% predicted, and impaired glucose tolerance to evaluate changes in glucose levels prior to the diagnosis of a pulmonary exacerbation. Results revealed elevated overnight, fasting and post-prandial glucose levels up to one week prior to diagnosis of a pulmonary exacerbation compared to baseline. In addition, mean glucose was elevated and the patient spent a greater percentage of time with interstitial glucose>140mg/dL up to one week prior to diagnosis of a pulmonary exacerbation. This emphasizes the hypothesis that hyperglycaemia may be a factor in pulmonary exacerbations in this population. This case study strengthens the evidence base to support larger longitudinal studies to understand the impact of glycaemic control and pulmonary function in patients with CF and glucose intolerance.

PMID: 28625799 [PubMed - as supplied by publisher]

Small Bowel Ultrasound beyond Inflammatory Bowel Disease: An Updated Review of the Recent Literature.

Ultrasound Med Biol. 2017 Jun 15;:

Authors: Cavalcoli F, Zilli A, Fraquelli M, Conte D, Massironi S

Abstract
The use of bowel ultrasonography (US) for the evaluation of gut diseases has increased in recent years and has been proven to provide a widely available, non-invasive and inexpensive method for the initial work-up and follow-up of different intestinal diseases, limited mostly by technical challenges posed by the patient's anatomy. The present review aims to provide an extensive overview of the main pathologic features at US examination of intestinal diseases other than inflammatory bowel disease, both acute (e.g., acute appendicitis, colonic diverticulitis, infectious diseases and ischemic conditions) and chronic (e.g., celiac disease, cystic fibrosis and other enterocolites). The identification of typical US features may help in the diagnostic process and guide the treatment approach. Therefore, the application of knowledge of the US appearance of gastrointestinal diseases is of relevance in enabling greater diagnostic performance and better patient management.

PMID: 28625560 [PubMed - as supplied by publisher]

Question 12: What do you consider when discussing treatment adherence in patients with Cystic Fibrosis?

Paediatr Respir Rev. 2017 Apr 27;:

Authors: Ohn M, Fitzgerald DA

PMID: 28625493 [PubMed - as supplied by publisher]

Oliver Smithies (1925-2017).

Nature. 2017 02 08;542(7640):166

Authors: Kucherlapati R

PMID: 28179651 [PubMed - indexed for MEDLINE]

Genomic analysis of melanoma evolution following a 30 year disease-free interval.

J Cutan Pathol. 2017 Jun 19;:

Authors: Miller JJ, Lofgren KA, Hughes SR, Cash SE, Kenny PA

Abstract
Ultra-late melanoma recurrence is infrequent, poorly understood and, in most cases, difficult to unambiguously distinguish from a new primary melanoma. We identified a patient with a second melanoma diagnosed after a 30 year disease-free interval, and sought to determine if this new lesion was a recurrence of the original melanoma. Here we report the genomic sequence analysis of the exomes of two melanoma lesions isolated from the same individual in 1985 and 2015, and their comparison to each other and to the germline DNA of the patient. Identification of many shared somatic mutations between these lesions prove a lineal relationship spanning 30 years. Unlike prior reports of ultra-late melanoma recurrence, the availability of the original tumor and the use of comprehensive genomic analysis allowed us to confirm that the second lesion is truly a recurrence. We demonstrate the acquisition of numerous additional mutations during the three decade asymptomatic period. These data highlight the low but very long-lasting risk of recurrence in this patient population.

PMID: 28628281 [PubMed - as supplied by publisher]

Clinical Applicability of Whole-Exome Sequencing Exemplified by a Study in Young Adults with the Advanced Cryptogenic Cholestatic Liver Diseases.

Gastroenterol Res Pract. 2017;2017:4761962

Authors: Kulecka M, Habior A, Paziewska A, Goryca K, Dąbrowska M, Ambrozkiewicz F, Walewska-Zielecka B, Gabriel A, Mikula M, Ostrowski J

Abstract
BACKGROUND: The proper use of new medical tests in clinical practice requires the establishment of their value and range of diagnostic usefulness. While whole-exome sequencing (WES) has already entered the medical practice, recognizing its diagnostic usefulness in multifactorial diseases has not yet been achieved.
AIMS: The objective of this study was to establish usability of WES in determining genetic background of chronic cholestatic liver disease (CLD) in young patients.
METHODS: WES was performed on six young patients (between 17 and 22 years old) with advanced fibrosis or cirrhosis due to CLD and their immediate families. Sequencing was performed on an Ion Proton sequencer.
RESULTS: On average, 19,673 variants were identified, of which from 7 to 14 variants of an individual were nonsynonymous, homozygous, recessively inherited, and considered in silico as pathogenic. Although monogenic cause of CLD has not been determined, several heterozygous rare variants and polymorphisms were uncovered in genes previously known to be associated with CLD, including ATP8B1, ABCB11, RXRA, and ABCC4, indicative of multifactorial genetic background.
CONCLUSIONS: WES is a potentially useful diagnostic tool in determining genetic background of multifactorial diseases, but its main limitation results from the lack of opportunities for direct linkage between the uncovered genetic variants and molecular mechanisms of disease.

PMID: 28626473 [PubMed - in process]

A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features.

J Med Genet. 2017 Jun 16;:

Authors: Marin-Valencia I, Novarino G, Johansen A, Rosti B, Issa MY, Musaev D, Bhat G, Scott E, Silhavy JL, Stanley V, Rosti RO, Gleeson JW, Imam FB, Zaki MS, Gleeson JG

Abstract
BACKGROUND: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain.
OBJECTIVE: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.
METHODS: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease.
RESULTS: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.
CONCLUSION: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.

PMID: 28626029 [PubMed - as supplied by publisher]

Tracking the Evolution of Non-Small-Cell Lung Cancer.

N Engl J Med. 2017 06 01;376(22):2109-2121

Authors: Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O'Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, Swanton C, TRACERx Consortium

Abstract
BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.
METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.
RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10(-4)), which remained significant in multivariate analysis.
CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

PMID: 28445112 [PubMed - indexed for MEDLINE]

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans.

PLoS One. 2016;11(10):e0165680

Authors: Kim BJ, Kim AR, Lee C, Kim SY, Kim NK, Chang MY, Rhee J, Park MH, Koo SK, Kim MY, Han JH, Oh SH, Park WY, Choi BY

Abstract
CDH23 mutations have mostly been associated with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic or nonsyndromic SNHL (DFNB12). Herein, we demonstrate the contribution of CDH23 mutations to postlingual nonsyndromic SNHL (NS-SNHL). We screened 32 Korean adult probands with postlingual NS-SNHL sporadically or in autosomal recessive fashion using targeted panel or whole exome sequencing. We identified four (12.5%, 4/32) potential postlingual DFNB12 families that segregated the recessive CDH23 variants, qualifying for our criteria along with rapidly progressive SNHL. Three of the four families carried one definite pathogenic CDH23 variant previously known as the prelingual DFNB12 variant in a trans configuration with rare CDH23 variants. To determine the contribution of rare CDH23 variants to the postlingual NS-SNHL, we checked the minor allele frequency (MAF) of CDH23 variants detected from our postlingual NS-SNHL cohort and prelingual NS-SNHL cohort, among the 2040 normal control chromosomes. The allele frequency of these CDH23 variants in our postlingual cohort was 12.5%, which was significantly higher than that of the 2040 control chromosomes (5.53%), confirming the contribution of these rare CDH23 variants to postlingual NS-SNHL. Furthermore, MAF of rare CDH23 variants from the postlingual NS-SNHL group was significantly higher than that from the prelingual NS-SNHL group. This study demonstrates an important contribution of CDH23 mutations to poslingual NS-SNHL and shows that the phenotypic spectrum of DFNB12 can be broadened even into the presbycusis, depending on the pathogenic potential of variants. We also propose that pathogenic potential of CDH23 variants and the clinical fate of DFNB12 may be predicted by MAF.

PMID: 27792758 [PubMed - indexed for MEDLINE]

Germline Variants of Prostate Cancer in Japanese Families.

PLoS One. 2016;11(10):e0164233

Authors: Hayano T, Matsui H, Nakaoka H, Ohtake N, Hosomichi K, Suzuki K, Inoue I

Abstract
Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family). We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family). We identified two deleterious HOXB13 variants (F127C and G132E). Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3). The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.

PMID: 27701467 [PubMed - indexed for MEDLINE]

Pharmacokinetic study of bortezomib administered intravenously in Taiwanese patients with multiple myeloma.

Hematol Oncol. 2017 Jun 19;:

Authors: Huang SY, Chang CS, Liu TC, Wang PN, Yeh SP, Ho CL, Kuo MC, Lin HY, de Jong J, Chen JY, Yang YW

Abstract
This phase 4, single-arm, non-randomized, open-label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m(2) , twice weekly for 2 weeks, followed by a 10-day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre-specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) Cmax (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non-Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half-life (t1/2 ), area under the plasma concentration-time curve from time 0 to infinity (AUC∞ ), volume of distribution (Vz ), and systemic clearance were not assessable. All patients experienced treatment-emergent adverse events (TEAEs); 78% were drug-related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUClast [SD]: 230 [147] ng·h/mL) with twice weekly intravenous administration was comparable with non-Asian population (AUClast [SD]: 241 [82] ng·h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy.

PMID: 28626947 [PubMed - as supplied by publisher]

Clomiphene for the treatment of male infertility: a case report of mood change.

Curr Drug Saf. 2017 Jun 15;:

Authors: Aussedat M, Jean-Louis J, Djahangirian O, Brochet MS

Abstract
BACKGROUND: Clomiphene is normally used in women with ovulatory dysfunction. In men, it is used off label in some cases of infertility. Psychological adverse effects are reported in women but very few in men.
CASE: A 34 year-old man treated with clomiphene for oligoteratospermia presented anxiety, decreased appetite, and depressed mood making him unable to function properly at work, five days after initiation of therapy. Symptoms required reduction followed by discontinuation of treatment four days later because of absence of improvement. Following cessation, the patient noted a gradual then a complete resolution approximately one week later. The patient did not have any psychiatric or other medical condition neither drug nor substance abuse that could explain this clinical presentation. The Naranjo's score was used to prove the clomiphene's imputability.
CONCLUSION: Health care providers should advise patients of the risk of psychological adverse effects when initiating treatment with clomiphene and should provide a close monitoring of mood change, especially during the initial weeks.

PMID: 28625145 [PubMed - as supplied by publisher]

[Icelanders' beliefs about medicines. Use of BMQ].

Laeknabladid. 2017 Februar;103(2):67-72

Authors: Vilhelmsdottir H, Johannsson M

Abstract
OBJECTIVE: To study beliefs held by the general public in Iceland about medicines.
METHODS: The Beliefs about Medicines Questionnaire was used to explore Icelanders' beliefs about medicines. A sample of 1500 Icelandic citizens, aged 18-75, obtained from the Social Science Research Insti-tute was given The Beliefs about Medicines Questionnaire.
RESULTS: The response rate was 61.6%. Most Icelanders have positive beliefs about their medication as well as general trust. Those who suffer from chronic diseases are more positive towards medicines than others and less inclined to view them as excessively used and harmful. Higher level of education predicts more positive beliefs towards medication - and vice versa. Gender and age do not seem to affect such beliefs.
CONCLUSION: Gaining a better understanding of people´s beliefs about medicines and what determines these beliefs can be of considerable value in the search for ways to improve therapy and adherence, espe-cially for those suffering from chronic diseases. Promoting education for the general public about medicines might result in less mis-understanding among patients and subsequently better grounded -beliefs and more adequate therapeutic adherence. Key words: beliefs, medicines, Icelanders, BMQ, survey. Correspondence: Hlif Vilhelmsdottir, hlif84@gmail.com.

PMID: 28489012 [PubMed - indexed for MEDLINE]

Medication governance: preventing errors and promoting patient safety.

Br J Nurs. 2017 Feb 09;26(3):159-165

Authors: Kavanagh C

Abstract
This article highlights the significance of medication errors, identifying potential issues and support systems required. Medication errors involve different health professionals and present at various stages of the medication cycle. Focusing on a collaborative approach and the role of the nurse is necessary. Special groups, particularly older adults, are considered where multiple conditions and multiple medications increase the risk of adverse drug reactions. Nurses' accountability and their knowledge of medications are taken into account along with the role of nurse educators. Reporting errors is crucial; the culture of the organisation significantly contributes to whether errors are reported. Learning arises from near misses and errors, enabling preventive measures to be put in place. There is a need for a culture of safety within organisations where medication governance promotes patient safety and the provision of high-quality care.

PMID: 28185490 [PubMed - indexed for MEDLINE]

Impact of Pharmacists in Optimizing Geriatric Pharmacotherapy in Primary Care Within a Veterans Affairs Medical Center.

Consult Pharm. 2017 Jan 01;32(1):47-62

Authors: Mondiello TB, Stutzman LA

Abstract
OBJECTIVE: To assess pharmacists' impact on optimizing pharmacotherapy among geriatric patients.
DESIGN: Single-site, prospective, quality-improvement project.
SETTING: Primary care at a Veterans Affairs medical center.
PARTICIPANTS: Thirteen males 75 years of age and older were included.
INTERVENTIONS: Recommendations were made by pharmacists to optimize prescribing.
MAIN OUTCOME MEASURES: Differences between specific instances of suboptimal prescribing before and after pharmacists' recommendations, the percentage of pharmacists' recommendations accepted, and the top most commonly prescribed psychotropic medications and their most common indications.
RESULTS: Sixty-three recommendations were made by pharmacists, and 48% of these recommendations were accepted by providers. There was a 27% reduction of the use of high-risk medications, a 44% reduction of omissions of care, and a 74% reduction of incomplete medication monitoring after pharmacists' recommendations. The most commonly prescribed psychotropic medications were zolpidem (31%), lorazepam (23%), and clonazepam and temazepam (each 15%). The most common indications for these medications were anxiety and insomnia (each 46%), with 8% of patients having an indication for both.
CONCLUSION: Pharmacists' recommendations improved geriatric pharmacotherapy by decreasing the overall instances of suboptimal prescribing.

PMID: 28077205 [PubMed - indexed for MEDLINE]