Literature Watch
Detection and monitoring of lung inflammation in cystic fibrosis during respiratory tract exacerbation using diffusion-weighted magnetic resonance imaging.
Detection and monitoring of lung inflammation in cystic fibrosis during respiratory tract exacerbation using diffusion-weighted magnetic resonance imaging.
Eur Respir J. 2017 Jul;50(1):
Authors: Ciet P, Bertolo S, Ros M, Andrinopoulou ER, Tavano V, Lucca F, Feiweier T, Krestin GP, Tiddens HAWM, Morana G
Abstract
The aim was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects and monitors inflammatory and lung function changes during respiratory tract exacerbations (RTE) treatment in patients with cystic fibrosis (CF).29 patients with RTE underwent DWI pre- and post-antibiotic treatment. A control group of 27 stable patients, matched for age and sex, underwent DWI with the same time gap as those undergoing RTE treatment. Clinical status and lung function were assessed at each DWI time point. The CF-MRI scoring system was used to assess structural lung changes in both CF groups.Significant reduction in the DWI score over the course of antibiotic treatment (p<0.0001) was observed in patients with RTE, but not in the control group. DWI score had a strong inverse correlation with clinical status (r=-0.504, p<0.0001) and lung function (r=-0.635, p<0.0001) in patients with RTE. Interestingly, there were persistent significant differences in the CF-MRI score between the RTE and control group at both baseline and follow-up (p<0.001), while the differences in DWI score were only observed at baseline (p<0.001).DWI is a promising imaging method for noninvasive detection of pulmonary inflammation during RTE, and may be used to monitor treatment efficacy of anti-inflammatory treatment.
PMID: 28729470 [PubMed - in process]
Congenital myopathy due to myosin heavy chain 2 mutation presenting as chronic aspiration pneumonia in infancy.
Congenital myopathy due to myosin heavy chain 2 mutation presenting as chronic aspiration pneumonia in infancy.
Neuromuscul Disord. 2017 Jun 27;:
Authors: Tsabari R, Daum H, Kerem E, Fellig Y, Dor T
Abstract
A 7-week-old infant presented with persistent noisy breathing and aspirations during swallowing. Neurological examination and brain MRI were normal. His 12-year-old brother underwent pneumonectomy at the age of 10 years due to recurrent aspirations leading to severe lung damage. The older brother developed subsequently ophthalmoplegia and nystagmus along with mild weakness of the neck flexors and proximal muscles. Exome analysis revealed homozygosity for a novel truncating mutation p.G800fs27* in the Myosin Heavy Chain 2 (MYH2) gene in both brothers, while parents and an unaffected sibling were heterozygous. A muscle biopsy from the older brother showed absence of type-2 muscle fibers and predominance of type-1 fibers. The aspirations causing pneumonia likely result from weakness of the laryngeal muscles, normally rich in type-2 fibers. The findings expand the phenotypic spectrum of MYH2 deficiency. MYH2 mutations should be included in the differential diagnosis of infants presenting with recurrent aspirations.
PMID: 28729039 [PubMed - as supplied by publisher]
Don't Push Your Luck! Educational Family Board (Not Bored) Game for School-Age Children Living with Chronic Conditions.
Don't Push Your Luck! Educational Family Board (Not Bored) Game for School-Age Children Living with Chronic Conditions.
J Pediatr Nurs. 2017 Jul - Aug;35:57-64
Authors: Kennedy A, Semple L, Alderson K, Bouskill V, Karasevich J, Riske B, van Gunst S
Abstract
PURPOSE: Children who are living with chronic conditions may be supported in self-care through enjoyable active learning and family social processes. This research focused on development and evaluation of "Don't Push Your Luck!", an educational board game designed to inspire family discussion about chronic conditions, and help affected children learn about self-care choices and consequences.
DESIGN AND METHODS: Mixed-method research was conducted with families from one outpatient Cystic Fibrosis Clinic and four Hemophilia Treatment Centres in Canada and United States (N=72). In phase I, board game prototype and questionnaires were refined with affected boys, siblings, and parents living with hemophilia (n=11), compared with families living with cystic fibrosis (n=11). In phase II, final board game was evaluated with families living with hemophilia (n=50). Data collection included pre-post-game questionnaires on decision-making and Haemo-QoL Index©, and post-game enjoyment. Analysis included descriptive statistics, inferential statistics (non-parametric), and qualitative themes.
RESULTS: Findings revealed this game was an enjoyable and effective resource to engage families in self-care discussions. Key themes included communication, being involved, knowing, decisions and consequences, and being connected. Qualitative and quantitative findings aligned. Statistical significance suggests the game enhanced family engagement to support decision-making skills, as parents identified that the game helped them talk about important topics, and children gained insight regarding family supports and self-care responsibility.
CONCLUSIONS: This board game was an effective, developmentally appropriate family resource to facilitate engagement and conversation about everyday life experiences in preparation for self-care.
PRACTICE IMPLICATIONS: There is promising potential to extend this educational family board game intervention with a greater range of school-age children and families living with chronic conditions.
PMID: 28728770 [PubMed - in process]
Disclosures of Cystic Fibrosis-Related Information to Romantic Partners.
Disclosures of Cystic Fibrosis-Related Information to Romantic Partners.
Qual Health Res. 2017 Aug;27(10):1575-1585
Authors: Broekema K, Weber KM
Abstract
In this article, we offer insights into how individuals with cystic fibrosis (CF) share information about their disease with a romantic partner. Using communication privacy management as a sensitizing theoretical construct, four themes emerged following 13 qualitative interviews with persons with CF. Themes about sharing CF-related information with a romantic partner include weighing the risks and benefits of sharing information, the role of health-related triggered rules, the motivations for disclosures, and the reactions from outsiders. Implications of the research suggest a need for more nuanced understandings of how privacy rules are communicated in relationships, how the mismanagement of co-owned information influences future disclosures, how the public-private nature of rare genetic illnesses is managed, and how people with genetic illnesses make disclosure decisions.
PMID: 28728531 [PubMed - in process]
Parental origin of the deletion del(20q) in Shwachman-Diamond patients and loss of the paternally derived allele of the imprinted L3MBTL1 gene.
Parental origin of the deletion del(20q) in Shwachman-Diamond patients and loss of the paternally derived allele of the imprinted L3MBTL1 gene.
Genes Chromosomes Cancer. 2017 Jan;56(1):51-58
Authors: Nacci L, Valli R, Maria Pinto R, Zecca M, Cipolli M, Morini J, Cesaro S, Boveri E, Rosti V, Corti P, Ambroni M, Pasquali F, Danesino C, Maserati E, Minelli A
Abstract
Shwachman-Diamond syndrome (SDS) (OMIM 260400) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, skeletal, and hematological abnormalities and bone marrow (BM) dysfunction. Mutations in the SBDS gene cause SDS. Clonal chromosome anomalies are often present in BM, i(7)(q10) and del(20q) being the most frequent ones. We collected 6 SDS cases with del(20q): a cluster of imprinted genes, including L3MBTL1 and SGK2 is present in the deleted region. Only the paternal allele is expressed for these genes. Based on these data, we made the hypothesis that the loss of this region, in relation to parental origin of deletion, may be of relevance for the hematological phenotype. By comparing hematological data of our 6 cases with a group of 20 SDS patients without evidence of del(20q) in BM, we observed a significant difference for Hb levels (P < 0.012), and a difference slightly above the significance level for RBC counts (P < 0.053): in both cases the values were higher in patients with del(20q). We also report preliminary evidence for an increased number of BFU-E colonies in cases with paternal deletion, data on the presence of the deletion in colonies and in mature circulating lymphocytes. © 2016 Wiley Periodicals, Inc.
PMID: 27553422 [PubMed - indexed for MEDLINE]
A homozygous MYO7A mutation associated to Usher syndrome and unilateral auditory neuropathy spectrum disorder.
A homozygous MYO7A mutation associated to Usher syndrome and unilateral auditory neuropathy spectrum disorder.
Mol Med Rep. 2017 Jul 21;:
Authors: Xia H, Hu P, Yuan L, Xiong W, Xu H, Yi J, Yang Z, Deng X, Guo Y, Deng H
Abstract
Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss, progressive visual loss and night blindness due to retinitis pigmentosa (RP), with or without vestibular dysfunction. The purpose of this study was to detect the causative gene in a consanguineous Chinese family with USH. A c.3696_3706del (p.R1232Sfs*72) variant in the myosin VIIa gene (MYO7A) was identified in the homozygous state by exome sequencing. The co‑segregation of the MYO7A c.3696_3706del variant with the phenotype of deafness and progressive visual loss in the USH family was confirmed by Sanger sequencing. The variant was absent in 200 healthy controls. Therefore, the c.3696_3706del variant may disrupt the interaction between myosin VIIa and other USH1 proteins, and impair melanosome transport in retinal pigment epithelial cells. Notably, bilateral auditory brainstem responses were absent in two patients of the USH family, while distortion product otoacoustic emissions were elicited in the right ears of the two patients, consistent with clinical diagnosis of unilateral auditory neuropathy spectrum disorder. These data suggested that the homozygous c.3696_3706del variant in the MYO7A gene may be the disease‑causing mutation for the disorder in this family. These findings broaden the phenotype spectrum of the MYO7A gene, and may facilitate understanding of the molecular pathogenesis of the disease, and genetic counseling for the family.
PMID: 28731162 [PubMed - as supplied by publisher]
Early Diagnosis of ABCB11 Spectrum Liver Disorders by Next Generation Sequencing.
Early Diagnosis of ABCB11 Spectrum Liver Disorders by Next Generation Sequencing.
Pediatr Gastroenterol Hepatol Nutr. 2017 Jun;20(2):114-123
Authors: Lee SJ, Kim JE, Choe BH, Seo AN, Bae HI, Hwang SK
Abstract
PURPOSE: The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis.
METHODS: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members.
RESULTS: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4(*)) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis.
CONCLUSION: ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.
PMID: 28730136 [PubMed]
A Chinese family with Axenfeld-Rieger syndrome: report of the clinical and genetic findings.
A Chinese family with Axenfeld-Rieger syndrome: report of the clinical and genetic findings.
Int J Ophthalmol. 2017;10(6):847-853
Authors: Sun DP, Dai YH, Pan XJ, Shan T, Wang DQ, Chen P
Abstract
AIM: To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in PITX2 in the family.
METHODS: Patients presented with typical ARS from a Chinese family were investigated. We performed genome-wide linkage scan and exome sequencing to identify the pathogenic mutations. Candidate mutations were verified for co-segregation in the whole pedigree using Sanger sequencing. Real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to verify the expression of the pathogenic gene.
RESULTS: Genome-wide linkage and exome sequencing analyses showed PITX2 as the disease candidate gene. A>G substitution at position -11 of 3'ss of exon 5 (IVS5-11A>G) that co-segregated with the disease phenotype was discovered in the family. The PITX2 messenger ribonucleic acid and protein levels were about 50% lower in patients with ARS than in unaffected family members in the family.
CONCLUSION: Our findings implicate the first intronic mutation of the PITX2 gene in the pathogenesis of a severe form of ARS in a Chinese family. This study highlights the importance of a systematic search for intronic mutation in ARS cases for which no mutations in the exons of PITX2 have been found.
PMID: 28730073 [PubMed]
The importance of managing the patient and not the gene: expanded phenotype of GLE1-associated arthrogryposis.
The importance of managing the patient and not the gene: expanded phenotype of GLE1-associated arthrogryposis.
Cold Spring Harb Mol Case Stud. 2017 Jul 20;:
Authors: Tan QK, McConkie-Rosell A, Juusola J, Gustafson KE, Pizoli CE, Buckley AF, Jiang YH
Abstract
GLE1 encodes a protein important for mRNA export and appears to play roles in translation initiation and termination as well. Pathogenic variants in GLE1 mutations have been associated with lethal contracture syndrome (LCCS1) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD); phenotypes reported in individuals include fetal akinesia and a severe form of motor neuron disease, typically presenting with prenatal symptoms and perinatal lethality. In this paper, we identified bi-allelic missense mutations in GLE1 by trio whole exome sequencing (WES) in an individual affected with congenital motor weakness and contractures as well as feeding and respiratory difficulties. Muscle biopsy was consistent with anterior horn cell disease and supported the pathogenicity of the sequence variants. Importantly, this individual survived past the perinatal period with respiratory support, and currently demonstrates age-appropriate cognition and slow but steady motor developmental progress. We propose that pathogenic variants in GLE1 can be associated with a non-perinatal lethal motor phenotype and affected individuals can demonstrate motor skill progression, unlike prototypical anterior horn cell diseases such as spinal muscular atrophy.
PMID: 28729373 [PubMed - as supplied by publisher]
Large-Scale Analysis of Drug Side Effects via Complex Regulatory Modules Composed of microRNAs, Transcription Factors and Gene Sets.
Large-Scale Analysis of Drug Side Effects via Complex Regulatory Modules Composed of microRNAs, Transcription Factors and Gene Sets.
Sci Rep. 2017 Jul 20;7(1):5962
Authors: Jia X, Jin Q, Liu X, Bian X, Wang Y, Liu L, Ma H, Tan F, Gu M, Chen X
Abstract
Identifying the occurrence mechanism of drug-induced side effects (SEs) is critical for design of drug target and new drug development. The expression of genes in biological processes is regulated by transcription factors(TFs) and/or microRNAs. Most of previous studies were focused on a single level of gene or gene sets, while studies about regulatory relationships of TFs, miRNAs and biological processes are very rare. Discovering the complex regulating relations among TFs, gene sets and miRNAs will be helpful for researchers to get a more comprehensive understanding about the mechanism of side reaction. In this study, a framework was proposed to construct the relationship network of gene sets, miRNAs and TFs involved in side effects. Through the construction of this network, the potential complex regulatory relationship in the occurrence process of the side effects was reproduced. The SE-gene set network was employed to characterize the significant regulatory SE-gene set interaction and molecular basis of accompanied side effects. A total of 117 side effects complex modules including four types of regulating patterns were obtained from the SE-gene sets-miRNA/TF complex regulatory network. In addition, two cases were used to validate the complex regulatory modules which could more comprehensively interpret occurrence mechanism of side effects.
PMID: 28729650 [PubMed - in process]
Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open...
Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study.
Lancet HIV. 2017 Jul 17;:
Authors: Orrell C, Hagins DP, Belonosova E, Porteiro N, Walmsley S, Falcó V, Man CY, Aylott A, Buchanan AM, Wynne B, Vavro C, Aboud M, Smith KY, ARIA study team
Abstract
BACKGROUND: Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1.
METHODS: The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402.
FINDINGS: Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1-17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications.
INTERPRETATION: The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women.
FUNDING: ViiV Healthcare.
PMID: 28729158 [PubMed - as supplied by publisher]
Using QR codes to enable quick access to information in acute cancer care.
Using QR codes to enable quick access to information in acute cancer care.
Br J Nurs. 2017 May 25;26(10):S4-S12
Authors: Upton J, Olsson-Brown A, Marshall E, Sacco J
Abstract
Quick access to toxicity management information ensures timely access to steroids/immunosuppressive treatment for cancer patients experiencing immune-related adverse events, thus reducing length of hospital stays or avoiding hospital admission entirely. This article discusses a project to add a QR (quick response) code to a patient-held immunotherapy alert card. As QR code generation is free and the immunotherapy clinical management algorithms were already publicly available through the trust's clinical network website, the costs of integrating a QR code into the alert card, after printing, were low, while the potential benefits are numerous. Patient-held alert cards are widely used for patients receiving anti-cancer treatment, and this established standard of care has been modified to enable rapid access of information through the incorporation of a QR code.
PMID: 28541108 [PubMed - indexed for MEDLINE]
Pharmacy Educators' Knowledge of Medication Safety and Their Perception Toward Its Integration into the Doctor of Pharmacy Curriculum in Saudi Arabia.
Pharmacy Educators' Knowledge of Medication Safety and Their Perception Toward Its Integration into the Doctor of Pharmacy Curriculum in Saudi Arabia.
Am J Pharm Educ. 2017 Mar 25;81(2):30
Authors: Alkatheri AM, Bustami R, Albekairy AM, Almodaimegh H, Alghamdi S, Alharbi S, Khalidi N, Murphy JE, Qandil AM
Abstract
Objective. To assess pharmacy educators' knowledge of medication safety and their perception toward its integration into the PharmD curriculum in Saudi Arabia. Methods. A survey was administered to pharmacy educators at a college of pharmacy and its affiliate hospital. Knowledge, training, and perception toward integrating medication safety into the PharmD curriculum were evaluated. Results. More than 50% of respondents indicated that medication safety should be covered within selected courses, and 65% indicated that such courses should be mandatory. Pharmacy practice educators had significantly higher levels of knowledge about medication safety than their nonpractice counterparts. Perceptions toward medication safety integration into the curriculum varied significantly by general discipline, academic degree, years of experience, and gender. Conclusion. Pharmacy educators in Saudi Arabia understand the importance of medication safety and its integration into the curriculum. Further studies are needed to guide curricular change to achieve this integration.
PMID: 28381890 [PubMed - indexed for MEDLINE]
Pioglitazone utilization, efficacy & safety in Indian type 2 diabetic patients: A systematic review & comparison with European Medicines Agency Assessment Report.
Pioglitazone utilization, efficacy & safety in Indian type 2 diabetic patients: A systematic review & comparison with European Medicines Agency Assessment Report.
Indian J Med Res. 2016 Nov;144(5):672-681
Authors: Pai SA, Kshirsagar NA
Abstract
BACKGROUND & OBJECTIVES: With pioglitazone ban and subsequent revoking in India along with varying regulatory decisions in other countries, it was decided to carry out a systematic review on its safety, efficacy and drug utilization in patients with type 2 diabetes mellitus (T2DM) in India and compare with the data from the European Medicines Agency Assessment Report (EMA-AR).
METHODS: Systematic review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching Medline/PubMed, Google Scholar and Science Direct databases using 'pioglitazone AND India AND human' and 'pioglitazone AND India AND human AND patient' and compared with EMA-AR. Spontaneous reports in World Health Organization VigiBase from India were compared with VigiBase data from other countries.
RESULTS: Sixty six publications, 26 (efficacy), 32 (drug utilization) and eight (safety), were retrieved. In India, pioglitazone was used at 15-30 mg/day mostly with metformin and sulphonylurea, being prescribed to 26.7 and 8.4 per cent patients in north and south, respectively. The efficacy in clinical trials (CTs) was similar to those in EMA-AR. Incidence of bladder cancer in pioglitazone exposed and non-exposed patients was not significantly different in an Indian retrospective cohort study. There were two cases and a series of eight cases of bladder cancer published but none reported in VigiBase.
INTERPRETATION & CONCLUSIONS: In India, probably due to lower dose, lower background incidence of bladder cancer and smaller sample size in epidemiological studies, association of bladder cancer with pioglitazone was not found to be significant. Reporting of CTs and adverse drug reactions to Clinical Trials Registry of India and Pharmacovigilance Programme of India, respectively, along with compliance studies with warning given in package insert and epidemiological studies with larger sample size are needed.
PMID: 28361819 [PubMed - indexed for MEDLINE]
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