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Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis.

Mycoses. 2018 Apr 27;:

Authors: Abdolrasouli A, Bercusson AC, Rhodes JL, Hagen F, Buil JB, Tang AYY, de Boer LL, Shah A, Milburn AJ, Elborn JS, Jones AL, Meis JF, Fisher MC, Schelenz S, Simmonds NJ, Armstrong-James D

Abstract
Infections caused by Rasamsonia argillacea complex have been reported in various clinical settings. Cystic fibrosis (CF) is one of the main underlying conditions. An observational cohort study of CF patients with Rasamsonia in respiratory samples was conducted. Eight isolates from six patients were identified as R. argillacea complex and tested for antifungal susceptibility. All isolates had high MICs to voriconazole and posaconazole and low MECs to echinocandins. Four patients experienced lung function decline in the year preceding first Rasamsonia isolation. This continued in the year following first isolation in three out of four cases. Antifungal therapy was initiated in two patients, to which only one exhibited a clinical response. Three out of six patients died within three years of isolating Rasamsonia. Genotyping suggests that similar genotypes of Rasamsonia can persist in CF airways. Consistent with other fungi in CF, the clinical impact of airway colonization by Rasamsonia is variable. In certain patients, Rasamsonia may be able to drive clinical decline. In others, though a clear impact on lung function may be difficult to determine, the appearance of Rasamsonia acts as a marker of disease severity. In others it does not appear to have an obvious clinical impact on disease progression. This article is protected by copyright. All rights reserved.

PMID: 29702751 [PubMed - as supplied by publisher]

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State of the Art in Pediatric Lung Transplantation.

Semin Thorac Cardiovasc Surg. 2018 Apr 24;:

Authors: Lancaster TS, Eghtesady P

Abstract
Pediatric lung transplantation is a highly specialized therapy for end stage pulmonary disease in children, performed in only a handful of transplant centers around the world. Advancement in the field has been made on many fronts in recent years, including in public policy and organ allocation strategies, donor selection and management, emerging technologies for donor lung rehabilitation and bridge-to-transplant support of listed candidates, and ongoing refinement of surgical techniques. Despite this progress, children continue to suffer discrepant waitlist mortality and longer waiting times than their adult counterparts, and face special challenges of donor availability and size matching. Here we review the current state of the art in pediatric lung transplantation, reviewing progress made to date and further opportunities to improve care for this unique group of patients.

PMID: 29702179 [PubMed - as supplied by publisher]

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Long term extra pulmonary comorbidities after lung transplantation in cystic fibrosis: update of specificities.

Clin Transplant. 2018 Apr 26;:e13269

Authors: Jardel S, Reynaud Q, Durieu I

Abstract
Lung transplantation (LT) is the standard therapeutic option for cystic fibrosis (CF) patients with end-stage lung disease. Both conditions lead to extra-respiratory complications, such as diabetes, renal insufficiency, bone disease, and cancer. The purpose of the present paper is to provide an update of the non-respiratory comorbidities following LT in adult patients with CF and their specificities regarding their multi-systemic underlying condition despite their younger age compared to other patients undergoing LT. Diabetes, renal insufficiency, metabolic bone disease, hypertension, liver disease and cancer are the comorbidities considered in this review. The increase of CF adults living with a lung transplant justifies an update of knowledge for this specific situation (prevalence of these complications, underlying risk factors), in order to provide better medical care and establish early diagnosis strategies. This article is protected by copyright. All rights reserved.

PMID: 29700855 [PubMed - as supplied by publisher]

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Recurrent haemoptysis in a child with advanced cystic fibrosis lung disease.

BMJ. 2018 Apr 26;361:k1142

Authors: O'Sullivan DM, Linnane B

PMID: 29700166 [PubMed - in process]

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Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family.

Mol Genet Genomic Med. 2018 Apr 26;:

Authors: Caulfield TR, Richter JE, Brown EE, Mohammad AN, Judge DP, Atwal PS

Abstract
BACKGROUND: Haploinsufficiency of TAB2 is known to cause congenital heart defects and cardiomyopathy due to its important roles in cardiovascular tissue, both during development and through adult life. We report a sibling pair displaying adult-onset cardiomyopathy, hypermobility, and mild myopia. Our proband, a 39-year-old male, presents only with the above symptoms, while his 36-year-old sister was also notable for a ventricular septal defect in her infancy.
METHODS: Whole-exome sequencing was utilized to identify the molecular basis of the phenotype found in two siblings. A molecular modeling technique that takes advantage of conformational sampling advances (Maxwell's demon molecular dynamics and Monte Carlo) were used to make a model of the mutant variant for comparative analytics to the wild-type.
RESULTS: Exome sequencing revealed a novel, heterogeneous pathogenic variant in TAB2, c.1039 C>T (p.R347X), that was present in both individuals. This pathogenic variant removes just over half the residues from the TAB2 protein and severely impacts its functional ability, which we describe in detail.
CONCLUSIONS: Analysis of the proband's family showed a history of cardiomyopathy, but no congenital heart defects or connective tissue disease. We highlight the heterogeneity in phenotype of TAB2 pathogenic variants and confirm the pathogenicity of this new variant through neoteric protein modeling techniques.

PMID: 29700987 [PubMed - as supplied by publisher]

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Method to Identify Silent Codon Mutations That May Alter Peptide Elongation Kinetics and Co-translational Protein Folding.

Methods Mol Biol. 2017;1647:237-243

Authors: Worthington R, Ball E, Wolf B, Takacs G

Abstract
Due to the redundancy of the protein genetic code, mutational changes in the second or third nucleotide of an existing codon may not change the amino acid specification of the resulting modified codon. When peptide primary sequence is unchanged by mutation, that mutation is assumed to have no functional consequences. However, for one key gene involved in drug transport, MDR-1, several silent, synonymous mutations have been shown to alter protein structure and substrate affinity (Kimchi-Sarfaty et al., Science 315:525-528, 2007). The mechanism of these changes, in the absence of primary amino acid sequence changes, appears to be the change in abundance of the transfer RNA molecules complementary to the mutated, although synonymous, new codon. Transfer RNA abundance is proportional to the frequency of each codon as found in human protein coding DNA (Sharp et al., Nucleic Acids Res 14(13):5125-5143, 1986). These frequencies have been mapped for many thousands of human proteins (Nakamura et al., Nucleic Acids Res 28:292, 2000). This method analyzes silent codon mutations in whole genome data. Where there are large changes in codon frequency resulting from codon sequence mutation, the affected proteins are mapped to potential disease pathways, in the context of clinical phenotypes associated with the patient genome data.

PMID: 28809007 [PubMed - indexed for MEDLINE]

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Adverse events of fluoroquinolones vs. other antimicrobials prescribed in primary care: A systematic review and meta-analysis of randomized controlled trials.

Int J Antimicrob Agents. 2018 Apr 24;:

Authors: Tandan M, Cormican M, Vellinga A

Abstract
BACKGROUND: Fluoroquinolones (FQs) are second line antimicrobial agents. Once the decision to prescribe an antimicrobial is made, its choice should be based on both the benefits and harms. This systematic review quantifies the occurrence of common adverse events (AEs) related to FQs in relation to any other antimicrobial for any indication in primary care.
METHODS: We searched randomized controlled trials from Embase, PubMed, Cochrane Central Register of Controlled Trials and CINHAL. FQs had to be administered orally, for any indication, to adults and in primary care. Data were extracted independently in standard forms in "Covidence". Pooled estimates of the intervention effects for AEs were determined by the Peto odds ratios (ORs) and 95% confidence intervals in Revman.
RESULTS: Of the 39 studies selected, the most commonly reported AEs were nausea, vomiting, diarrhoea, headache, dizziness, and rash. A meta-analysis of 28 studies reporting AEs showed central nervous system (CNS) (OR 1.40 (1.12-1.75) p=0.003, heterogeneity (I2) = 0%) and gastrointestinal (GI) related AEs (OR 1.20 (1.06-1.36) p=0.005, I2=80%) were significantly associated with FQs use compared to other antimicrobials. Compared to FQs, co-amoxiclav showed significantly more total AEs (OR 0.70 (0.54-0.90) p=0.006, I2=78%) and GI-related AEs (OR 0.69(0.52-0.91) p=0.008, I2=94%). Withdrawal and/or discontinuation due to drug-related AEs were higher for FQs (OR 1.19 (1.00-1.42) p=0.05, I2=5%). Sensitivity analyses did not change these results.
CONCLUSION: FQs are associated with more CNS and GI-related AEs compared to other types of antimicrobial. This information is relevant to support decision making in relation to antimicrobial prescribing.

PMID: 29702230 [PubMed - as supplied by publisher]

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Calcium channel blockers for antipsychotic-induced tardive dyskinesia.

Cochrane Database Syst Rev. 2018 03 26;3:CD000206

Authors: Essali A, Soares-Weiser K, Bergman H, Adams CE

Abstract
BACKGROUND: Schizophrenia and related disorders affect a sizable proportion of any population. Antipsychotic medications are the primary treatment for these disorders. Antipsychotic medications are associated with a variety of adverse effects including tardive dyskinesia. Dyskinesia is a disfiguring movement disorder of the orofacial region that can be tardive (having a slow or belated onset). Tardive dyskinesia is difficult to treat, despite experimentation with several treatments. Calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil, flunarizine) have been among these experimental treatments.
OBJECTIVES: To determine the effects of calcium channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses.
SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information.
SELECTION CRITERIA: We selected randomised controlled trials comparing calcium channel blockers with placebo, no intervention or any other intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness who remained on their antipsychotic medication.
DATA COLLECTION AND ANALYSIS: We independently extracted data and estimated risk ratios of dichotomous data or mean differences (MD) of continuous data, with 95% confidence intervals (CI). We assumed that people who left the trials early had no improvement. We also created a 'Summary of findings' table using GRADE.
MAIN RESULTS: Previous versions of this review included no trials. From the 2015 search, we identified three cross-over trials that could be included. The 2017 search found no new studies relevant to this review. The included trials randomised 47 inpatients with chronic mental illnesses in the USA and China. Trials were published in the 1990s and were of short duration (six to 10 weeks). Overall, the risk of bias was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, and attrition and outcome data were not fully reported. Findings were sparse, no study reported on the primary outcome 'no clinically important improvement in tardive dyskinesia symptoms,' but two small studies (37 participants) found no difference on the tardive dyskinesia symptoms scale Abnormal Involuntary Movement Scale (AIMS) scores between diltiazem or flunarizine and placebo after three to four weeks' treatment (MD -0.71, 95% CI -2.68 to 1.26, very low quality evidence). Only one study randomising 20 participants reported on adverse events, and reported that there were no adverse events with flunarizine or with placebo (very low quality evidence). One study with 18 participants reported no events of deterioration in mental state with diltiazem or with placebo (very low quality evidence). No studies reported on acceptability of treatment or on social confidence, social inclusion, social networks or personalised quality of life outcomes designated important to patients.
AUTHORS' CONCLUSIONS: Available evidence from randomised controlled trials is extremely limited and very low quality, conclusions cannot be drawn. The effects of calcium channel blockers for antipsychotic-induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well-designed randomised trials.

PMID: 29578611 [PubMed - indexed for MEDLINE]

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Evaluating quality of life in epilepsy: The role of screening for adverse drug effects, depression, and anxiety.

Epilepsy Behav. 2017 Oct;75:18-24

Authors: Micoulaud-Franchi JA, Bartolomei F, Duncan R, McGonigal A

Abstract
OBJECTIVE: The objective of this study was to evaluate the contribution of validated screening tools for antiepileptic drug (AED) adverse effects, depression, and anxiety to measure the quality of life (QoL) in people with epilepsy (PWE).
METHODS: Patients in a tertiary epilepsy service were screened for quality of life (using QOLIE-31), major depressive disorder (MDD) (NDDI-E), generalized anxiety disorder (GAD) (GAD-7), and AED effects (AEP). Mini International Neuropsychiatric Interview (MINI) generalized anxiety disorder module was also performed. For AEP validation in French, the internal structural validity was analyzed. Dimensional (NDDI-E and GAD-7 scores) and categorical (MDD and GAD) analyses were performed to investigate interactions between QoL and AEP.
RESULTS: A total of 132 (87 females) subjects were included. The French version of the AEP demonstrated satisfactory psychometric properties (Cronbach's α 0.87). Correlations between NDDI-E, GAD-7, AEP, and QOLIE-31 scores were high, and significant for all subscales of QOLIE-31; no effect of seizure-related variables was seen. Some sex differences in QOLIE-31 subscales were found, and mean AEP score was higher in females. Age, sex, NDDI-E, GAD-7, and AEP scores accounted for 61% of variance of QOLIE-31 scores. Differential effects were seen on QOLIE-31 subscales: AEP strongly correlated with all subscales; GAD-7 scores more strongly correlated with "Seizure Worry"; NDDI-E with "Energy-Fatigue"; and both NDDI-E and GAD-7 scores strongly correlated with "Emotional Well-Being". Categorical analysis of groups with MDD alone, GAD alone, MDD+GAD, and neither MDD nor GAD showed significant differences in AEP and QOLIE-31 scores, with MDD+GAD showing the most AED effects and the poorest QoL.
SIGNIFICANCE: The combination of screening tools for depression (NDDI-E), anxiety (GAD-7), and AED effects (AEP) has a strong power for evaluating QoL in PWE. Coexisting MMD and GAD were associated with the poorest quality of life and the highest AEP scores.

PMID: 28818810 [PubMed - indexed for MEDLINE]

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Safety of Cancer Therapies: At What Cost?

Popul Health Manag. 2017 Aug;20(4):318-328

Authors: Fitzner K, Oteng-Mensah F, Donley P, Heckinger EAF

Abstract
The cost of cancer drugs has increased concurrently with drug safety resulting in both increased survivorship and increased out-of-pocket costs and co-payments for patients. This article evaluates the interplay between patient safety and cancer drug costs to determine how cancer drug costs affect patient safety and well-being. A literature review was performed that identified the main drivers of drug safety costs: drug-drug interactions, adverse drug events, medication errors, and nonadherence. Three main types of costs were identified: out-of-pocket spending, drug cost growth, and safety-related costs. Insured patients receiving chemotherapy pay an average of $10,000/month on out-of-pocket expenses. Annual drug cost growth has been as much as 21% in recent years. Over a span of 13 years, 1999-2013, insurance premiums and out-of-pocket payments have increased by 182% and 200%, respectively. Safety-related concerns include the high cost of developing a new drug, estimated at $5 billion. The cost of development is reflected in the cost of the 12 new cancer drugs that received Food and Drug Administration approval in 2012; 11 were priced at 6 figures. Although advances in pharmaceutical technology and research have yielded effective cancer therapies that reduce physical or treatment-related toxicity, patients have had to face worsening financial uncertainty both during and after treatment. Actions are needed to achieve financial safety, as well as therapeutic and clinical safety, for cancer patients.

PMID: 28112578 [PubMed - indexed for MEDLINE]

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Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in children: 20 years study in a tertiary care hospital.

World J Pediatr. 2017 Jun;13(3):255-260

Authors: Techasatian L, Panombualert S, Uppala R, Jetsrisuparb C

Abstract
BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe lifethreatening skin conditions. The most common cause of these manifestations is medications. Beside discontinued of the culprit drug, systemic corticosteroids were used as a primary treatment option among pediatric population. This study aimed to explore causative drugs (drug group/ latent period), treaments, complications, and treatment outcome (morbidity, mortality, length of hospital stay) of SJS and TEN in children.
METHODS: A retrospective chart was reviewed during the period of 1992 to 2012 at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand. SJS and TEN were clinically diagnosed and confirmed by pediatric dermatologists. Other possible causes other than druginduced SJS and TEN were excluded.
RESULTS: A total of 30 patients was recorded, including 24 (80%) SJS patients and 6 (20%) TEN patients. The mean age was 6.9 years (SD 4.4). Male to female ratio was 1.5:1. Antiepileptic drug group was the most common causative drug (n=18, 60%), followed by antibiotic drug group (n=8, 26.6%), and others (n=4, 13.3%) which included nonsteroidal antiinflammtory drugs (NSAIDs) and chemotherapy drugs. Systemic corticosteroids were used in 29 patients (96.6%). Intravenous immunoglobulin was used in one TEN patient (3.3%). There was a medium correlation between time to treatment (systemic corticosteroids) and the length of hospital stay (Spearman correlation coefficient=0.63, P=0.005). Two TEN patients (6.6%) died.
CONCLUSIONS: Carbamazepine was the most common causative drug of SJS and TEN in our study. The severity of skin detachment is not correlated to severity of ocular findings. However, the persistent of ocular complications up to one year is suggested for promptly appropriate ocular treatment in all SJS and TEN patients. Our data suggested that early administration of systemic corticosteroid may reduce the length of hospital stay and should be considered for the treatment of pediatric druginduced SJS and TEN.

PMID: 27650525 [PubMed - indexed for MEDLINE]

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Meaningful Use IT reduces hospital-caused adverse drug events even at challenged hospitals.

Healthc (Amst). 2015 Mar;3(1):12-7

Authors: Encinosa WE, Bae J

Abstract
BACKGROUND: many Meaningful Use (MU) requirements involve medication management. Little is known about what impact these will have on adverse drug events (ADEs) at challenged hospitals.
METHODS: we use the Florida State Inpatient Database (HCUP, AHRQ), the AHA IT Supplement, and Hospital Compare. Controlling for non-response selection bias, we use multi-level GLLAMM regression analysis to examine the impact of the 5 core MU medication elements on hospital-caused ADEs.
RESULTS: adopting all 5 core MU elements was associated with a reduction in ADEs. Hospitals reporting costs as the main barrier to MU reduced their ADE rates by 35%; low quality hospitals reduced ADEs by 29%, compared to 27% at high quality hospitals. Among hospitals reporting these medication elements among their top MU challenges, ADEs were reduced by 69%, compared to 45% for hospitals with no drug functions as their top MU challenges. However, ADEs increased by 14% at hospitals with physician resistance to MU, compared to a 52% ADE reduction without physician resistance.
CONCLUSIONS: the bundling all five medication functions in MU is associated with large reductions in ADEs.
IMPLICATIONS: without physician buy-in at the hospital, MU will have no impact on ADEs.

PMID: 26179584 [PubMed - indexed for MEDLINE]

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Notice NOT-AI-18-033 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-HL-19-023 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA) is to enhance the participation of individuals from diverse backgrounds underrepresented in cardiovascular, pulmonary, hematologic and sleep disorders research across the career development continuum. The NHLBIs T32 Training Program for Institutions That Promote Diversity is a Ruth L. Kirschstein National Research Service Award Program intended to support training of predoctoral and health professional students and individuals in postdoctoral training institutions with an institutional mission focused on serving health disparity populations not well represented in scientific research, or institutions that have been identified by federal legislation as having an institutional mission focused on these populations, with the potential to develop meritorious training programs in cardiovascular, pulmonary, and hematologic diseases, and sleep disorders. The NHLBIs T32 Training Program for Institutions That Promote Diversity is designed to expand the capability for biomedical research by providing grant support to institutions that have developed successful programs that promote diversity, serve health disparity populations, and that offer doctoral degrees in the health professions or in health-related sciences. These institutions are uniquely positioned to engage minority and other health disparity populations in research, translation, and implementation of research advances that impact health outcomes, as well as provide health care for these populations. This Funding Opportunity Announcement (FOA) does not allow appointed Trainees to lead an independent clinical trial, but does allow them to obtain research experience in a clinical trial led by a mentor or co-mentor.

Notice NOT-NS-18-060 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-766 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages research grant applications focusing on identification and management of behavioral symptoms and mental health conditions in individuals with intellectual disabilities (ID). Specific areas of interest for this funding opportunity are (1) proposals to develop and validate assessment tools that reliably identify behavioral symptoms or diagnose mental health conditions in individuals with ID, and (2) proposals studying the pharmacokinetics, safety and efficacy of specific psychotropic medications for treatment of behavioral symptoms or mental health conditions in individuals with ID.

Funding Opportunity RFA-CA-18-026 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to reduce the burden of cancer and improve the quality of cancer care in rural areas among low-income and/or underserved populations. The FOA encourages two types of applications: 1) observational research that includes pilot testing of intervention to understand and address predictors of cancer care/treatment and outcomes in rural low-income and/or underserved populations, or 2) intervention research to address known predictors of cancer care/treatment and outcomes in rural low-income and/or underserved populations. Specifically, the focus for observational studies (with pilot testing) is understanding and addressing the predictive and/or mediating role of social determinants of health, barriers to care, and treatment; and the focus for interventional research is on addressing quality of care related to cancer diagnosis, treatment and/or survivorship. Most existing cancer control interventions are not ready for direct implementation and dissemination in low-income rural areas, so proposals should seek to develop, adapt, and/or implement, and test interventions.

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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