Literature Watch
Pediatric Lung Transplantation.
Pediatric Lung Transplantation.
Respir Care. 2017 Jun;62(6):776-798
Authors: Sweet SC
Abstract
Pediatric lung transplant is a viable option for treatment of end-stage lung disease in children, with > 100 pediatric lung transplants reported to the Registry of the International Society of Heart and Lung Transplantation each year. Long-term success is limited by availability of donor organs, debilitation as a result of chronic disease, impaired mucus clearance resulting from both surgical and pharmacologic interventions, increased risk for infection resulting from immunosuppression, and most importantly late complications, such as chronic lung allograft dysfunction. Opportunities for investigation and innovation remain in all of these domains: (1) Ex vivo lung perfusion is a promising technology with the potential for increasing the lung donor pool, (2) evolving extracorporeal support strategies coupled with effective rehabilitation will effectively bridge critically ill patients to transplant, and most importantly, (3) research efforts intended to increase our understanding of the underlying mechanisms of chronic lung allograft dysfunction will ultimately lead to the development of effective therapies to prevent or treat the variety of chronic lung allograft dysfunction presentations.
PMID: 28546378 [PubMed - in process]
MRI of cystic fibrosis lung manifestations: sequence evaluation and clinical outcome analysis.
MRI of cystic fibrosis lung manifestations: sequence evaluation and clinical outcome analysis.
Clin Radiol. 2017 May 22;:
Authors: Scholz O, Denecke T, Böttcher J, Schwarz C, Mentzel HJ, Streitparth F, Maurer MH, Pfeil A, Huppertz A, Mehl A, Staab D, Hamm B, Renz DM
Abstract
AIM: To evaluate different magnetic resonance imaging (MRI) sequences for diagnosis of pulmonary manifestations of cystic fibrosis (CF) in comparison to chest computed tomography (CT), including an extended outcome analysis.
MATERIALS AND METHODS: Twenty-eight patients with CF (15 male, 13 female, mean age 30.5±9.4 years) underwent CT and MRI of the lung. MRI (1.5 T) included different T2- and T1-weighted sequences: breath-hold HASTE (half Fourier acquisition single shot turbo spin echo) and VIBE (volumetric interpolated breath-hold examination, before and after contrast medium administration) sequences and respiratory-triggered PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) sequences with and without fat signal suppression, and perfusion imaging. CT and MRI images were evaluated by the modified Helbich and the Eichinger scoring systems. The clinical follow-up analysis assessed pulmonary exacerbations within 24 months.
RESULTS: The highest concordance to CT was achieved for the PROPELLER sequences without fat signal suppression (concordance correlation coefficient CCC of the overall modified Helbich score 0.93 and of the overall Eichinger score 0.93). The other sequences had the following concordance: PROPELLER with fat signal suppression (CCCs 0.91 and 0.92), HASTE (CCCs 0.87 and 0.89), VIBE (CCCs 0.84 and 0.85) sequences. In the outcome analysis, the combined MRI analysis of all five sequences and a specific MRI protocol (PROPELLER without fast signal suppression, VIBE sequences, perfusion imaging) reached similar correlations to the number of pulmonary exacerbations as the CT examinations.
CONCLUSION: An optimum lung MRI protocol in patients with CF consists of PROPELLER sequences without fat signal suppression, VIBE sequences, and lung perfusion analysis to enable high diagnostic efficacy and outcome prediction.
PMID: 28545684 [PubMed - as supplied by publisher]
A simple, fast and inexpensive method for mutation scanning of CFTR gene.
A simple, fast and inexpensive method for mutation scanning of CFTR gene.
BMC Med Genet. 2017 May 25;18(1):58
Authors: Figueredo Lago JE, Armas Cayarga A, González González YJ, Collazo Mesa T
Abstract
BACKGROUND: Mutation scanning methods in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene may not distinguish between a Cystic Fibrosis (CF) causing mutation and a benign variant. We have developed a simple and fast method for scanning 14 selected CF-causing mutations which have high frequency in Latin America.
METHODS: In a group of 35 samples coming from CF patients previously characterized and using two allele-specific real-time multiplex PCRs targeting wild-type and mutant alleles respectively, we detect the presence of mutations by analyzing the Ct variation. Twenty-five samples without mutations considered non-carrier samples, were also included in this study. High Resolution Melting Analysis (HRMA) was performed to confirm the result of the scanning method and in most cases allowed the genotype determination.
RESULTS: The results validate this method for CF diagnosis. A least one CFTR gene mutation was detected in the samples of CF patients, as predicted by their ΔCt values. The ΔCt value also indicated the zygosity of the sample according to the distribution of CFTR gene mutations. In most cases, HRMA allowed the identification of the mutation(s), thereby confirming the efficiency of this scanning strategy.
CONCLUSIONS: This strategy simplifies the detection of CF, reducing the analysis of 14 CF-causing mutations to two parallel reactions and making the procedure compatible with the analysis of a large number of samples. As the method is fast, inexpensive and highly reliable, it is advisable for scanning CFTR gene mutations in newborns, patients with a clinical suspicion of CF as well as in the preconception carrier screening.
PMID: 28545452 [PubMed - in process]
ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.
ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.
Brain. 2017 Jun 01;140(6):1595-1610
Authors: Desai R, Frazier AE, Durigon R, Patel H, Jones AW, Dalla Rosa I, Lake NJ, Compton AG, Mountford HS, Tucker EJ, Mitchell ALR, Jackson D, Sesay A, Di Re M, van den Heuvel LP, Burke D, Francis D, Lunke S, McGillivray G, Mandelstam S, Mochel F, Keren B, Jardel C, Turner AM, Ian Andrews P, Smeitink J, Spelbrink JN, Heales SJ, Kohda M, Ohtake A, Murayama K, Okazaki Y, Lombès A, Holt IJ, Thorburn DR, Spinazzola A
Abstract
Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Although high homology complicates genomic analysis of the ATAD3 defects, they can be identified by targeted analysis of standard single nucleotide polymorphism array and whole exome sequencing data. We report deletions that generate chimeric ATAD3B/ATAD3A fusion genes in individuals from four unrelated families with fatal congenital pontocerebellar hypoplasia, whereas a case with genomic rearrangements affecting the ATAD3C/ATAD3B genes on one allele and ATAD3B/ATAD3A genes on the other displays later-onset encephalopathy with cerebellar atrophy, ataxia and dystonia. Fibroblasts from affected individuals display mitochondrial DNA abnormalities, associated with multiple indicators of altered cholesterol metabolism. Moreover, drug-induced perturbations of cholesterol homeostasis cause mitochondrial DNA disorganization in control cells, while mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann-Pick type C disease further corroborates the interdependence of mitochondrial DNA organization and cholesterol. These data demonstrate the integration of mitochondria in cellular cholesterol homeostasis, in which ATAD3 plays a critical role. The dual problem of perturbed cholesterol metabolism and mitochondrial dysfunction could be widespread in neurological and neurodegenerative diseases.
PMID: 28549128 [PubMed - in process]
A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States.
A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States.
Invest Ophthalmol Vis Sci. 2017 May 01;58(5):2774-2784
Authors: Sullivan LS, Bowne SJ, Koboldt DC, Cadena EL, Heckenlively JR, Branham KE, Wheaton DH, Jones KD, Ruiz RS, Pennesi ME, Yang P, Davis-Boozer D, Northrup H, Gurevich VV, Chen R, Xu M, Li Y, Birch DG, Daiger SP
Abstract
Purpose: To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG.
Methods: Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members.
Results: Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability.
Conclusions: This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.
PMID: 28549094 [PubMed - in process]
Whole exome sequencing of a patient with suspected mitochondrial myopathy reveals novel compound heterozygous variants in RYR1.
Whole exome sequencing of a patient with suspected mitochondrial myopathy reveals novel compound heterozygous variants in RYR1.
Mol Genet Genomic Med. 2017 May;5(3):295-302
Authors: Blackburn PR, Selcen D, Gass JM, Jackson JL, Macklin S, Cousin MA, Boczek NJ, Klee EW, Dimberg EL, Kennelly KD, Atwal PS
Abstract
BACKGROUND: Pathogenic variants in ryanodine receptor 1 (RYR1, MIM# 180901) are the cause of congenital myopathy with fiber-type disproportion, malignant hyperthermia susceptibility type 1, central core disease of muscle, multiminicore disease and other congenital myopathies.
METHODS: We present a patient with global developmental delay, hypotonia, myopathy, joint hypermobility, and multiple other systemic complaints that were noted early in life. Later she was found to have multiple bone deformities involving her spine, with severe scoliosis that was corrected surgically. She was also diagnosed with ophthalmoplegia, chronic hypercapnic respiratory failure, and hypertension. At 22 years of age she presented to the genetics clinic with a diagnosis of mitochondrial myopathy and underwent whole exome sequencing (WES).
RESULTS: Whole exome sequencing revealed two novel compound heterozygous variants in RYR1 (c.7060_7062del, p.Val2354del and c.4485_4500del, p.Tyr1495X).
CONCLUSION: Review of her clinical, pathologic, and genetic findings pointed to a diagnosis of a congenital myopathy with fiber-type disproportion.
PMID: 28547000 [PubMed - in process]
Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias.
Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias.
Mol Genet Genomic Med. 2017 May;5(3):280-286
Authors: Bis DM, Schüle R, Reichbauer J, Synofzik M, Rattay TW, Soehn A, de Jonghe P, Schöls L, Züchner S
Abstract
BACKGROUND: The genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrier-parent. Detection of UPD-caused homozygous disease-causing variants is detrimental to accurate genetic counseling. Whole-exome sequencing can allow for the detection of such events.
METHODS: We systematically studied the exomes of a phenotypically heterogeneous cohort of unresolved cases (n = 96 families) to reveal UPD events hindering a diagnosis and to evaluate the prevalence of UPD in recessive MND and ATX.
RESULTS: One hereditary spastic paraplegia case harbored homozygous regions spanning 80% of chromosome 16. A homozygous disease-causing mutation in the SPG35 disease gene was then identified within this region.
CONCLUSION: This study demonstrates the ability to detect UPD in exome data of index patients. Our results suggest that UPD is a rare mechanism for recessive MND and ATX.
PMID: 28546998 [PubMed - in process]
Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients.
Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients.
Mol Genet Genomic Med. 2017 May;5(3):269-279
Authors: Cousin MA, Matey ET, Blackburn PR, Boczek NJ, McAllister TM, Kruisselbrink TM, Babovic-Vuksanovic D, Lazaridis KN, Klee EW
Abstract
BACKGROUND: We characterized the pharmacogenomics (PGx) results received by diagnostic odyssey patients as secondary findings during clinical whole exome sequencing (WES) testing as a part of their care in Mayo Clinic's Individualized Medicine Clinic to determine the potential benefits and limitations to this cohort.
METHODS: WES results on 94 patients included a subset of PGx variants in CYP2C19,CYP2C9, and VKORC1 if identified in the patient. Demographic, phenotypic, and medication usage information was abstracted from patient medical data. A pharmacist interpreted the PGx results in the context of the patients' current medication use and made therapeutic recommendations.
RESULTS: The majority was young with a median age of 10 years old, had neurological involvement in the disease presentation (71%), and was currently taking medications (90%). Of the 94 PGx-evaluated patients, 91% had at least one variant allele reported and 20% had potential immediate implications on current medication use.
CONCLUSION: Due to the disease complexity and medication needs of diagnostic odyssey patients, there may be immediate benefit obtained from early life PGx testing for many and most will likely find benefit in the future. These results require conscientious interpretation and management to be actionable for all prescribing physicians throughout the lifetime of the patient.
PMID: 28546997 [PubMed - in process]
Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia.
Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia.
Mol Genet Genomic Med. 2017 May;5(3):202-209
Authors: Toral MA, Velez G, Boudreault K, Schaefer KA, Xu Y, Saffra N, Bassuk AG, Tsang SH, Mahajan VB
Abstract
BACKGROUND: Foveal hypoplasia (FH) in the absence of albinism, aniridia, microphthalmia, or achromatopsia is exceedingly rare, and the molecular basis for the disorder remains unknown. FH is characterized by the absence of both the retinal foveal pit and avascular zone, but with preserved retinal architecture. SLC38A8 encodes a sodium-coupled neutral amino acid transporter with a preference for glutamate as a substrate. SLC38A8 has been linked to FH. Here, we describe a novel mutation to SLC38A8 which causes FH, and report the novel use of OCT-angiography to improve the precision of FH diagnosis. More so, we used computational modeling to explore possible functional effects of known SLC38A8 mutations.
METHODS: Fundus autofluorescence, SD-OCT, and OCT-angiography were used to make the clinical diagnosis. Whole-exome sequencing led to the identification of a novel disease-causing variant in SLC38A8. Computational modeling approaches were used to visualize known SLC38A8 mutations, as well as to predict mutation effects on transporter structure and function.
RESULTS: We identified a novel point mutation in SLC38A8 that causes FH. A conclusive diagnosis was made using OCT-angiography, which more clearly revealed retinal vasculature penetrating into the foveal region. Structural modeling of the channel showed the mutation was near previously published mutations, clustered on an extracellular loop. Our modeling also predicted that the mutation destabilizes the protein by altering the electrostatic potential within the channel pore.
CONCLUSION: Our results demonstrate a novel use for OCT-angiography in confirming FH, and also uncover genotype-phenotype correlations of FH-linked SLC38A8 mutations.
PMID: 28546991 [PubMed - in process]
A novel PRKAG2 mutation in a Chinese family with cardiac hypertrophy and ventricular pre-excitation.
A novel PRKAG2 mutation in a Chinese family with cardiac hypertrophy and ventricular pre-excitation.
Sci Rep. 2017 May 25;7(1):2407
Authors: Yang KQ, Lu CX, Zhang Y, Yang YK, Li JC, Lan T, Meng X, Fan P, Tian T, Wang LP, Liu YX, Zhang X, Zhou XL
Abstract
PRKAG2 syndrome is a rare autosomal dominant inherited disorder that is characterized by cardiac hypertrophy, ventricular pre-excitation and conduction system abnormalities. There is little knowledge in cardiovascular magnetic resonance (CMR) characteristics of PRKAG2 cardiomyopathy. This study investigated the genetic defect in a three-generation Chinese family with cardiac hypertrophy and ventricular pre-excitation using whole-exome sequencing. A novel missense mutation, c.1006 G > T (p.V336L), was identified in PRKAG2. This mutation had not been identified in the ExAC database, and the prediction result of MutationTaster indicated a deleterious effect. Furthermore, it cosegregated with the disease in the present family and was absent in unrelated 300 healthy controls. cDNA analysis did not detect any splicing defects, although the variant occurred in the first base of exon 9. CMR evaluation in five affected members showed diffuse hypertrophy in a concentric pattern, with markedly increased left ventricular mass above age and gender limits (median 151.3 g/m(2), range 108.4-233.4 g/m(2)). Two patients in progressive stage and one patient with sudden cardiac death exhibited extensive subendocardial late gadolinium enhancement. In conclusion, molecular screening for PRKAG2 mutations should be considered in patients who exhibit cardiac hypertrophy coexisting with ventricular pre-excitation. CMR offers promising advantages for evaluation of PRKAG2 cardiomyopathy.
PMID: 28546535 [PubMed - in process]
"Omic" Approach in Non-Smoker Female with Lung Squamous Cell Carcinoma Pinpoints to Germline Susceptibility and Personalized Medicine.
"Omic" Approach in Non-Smoker Female with Lung Squamous Cell Carcinoma Pinpoints to Germline Susceptibility and Personalized Medicine.
Cancer Res Treat. 2017 May 26;:
Authors: Baldassarri M, Fallerini C, Cetta F, Ghisalberti M, Bellan C, Furini S, Spiga O, Crispino S, Gotti G, Ariani F, Paladini P, Renieri A, Frullanti E
Abstract
Purpose: Lung cancer is strongly associated to tobacco smoking. However, global statistics estimate that in females the proportion of lung cancer cases that is unrelated to tobacco smoking reaches fifty percent, making questionable the etiology of the disease.
Materials and Methods: A never-smoker female with primary EGFR/KRAS/ALK-negative squamous cell carcinoma of the lung and their normal sibs were subjected to a novel integrative "omic" approach using a pedigree-based model for discovering genetic factors leading to cancer in the absence of well-known environmental trigger. A first-step whole-exome sequencing on tumor and normal tissue did not identify mutations in known driver genes. Building on the idea of a germline oligogenic origin of lung cancer, we performed whole-exome sequencing of DNA from patients' peripheral blood and their unaffected sibs. Finally, RNA-sequencing analysis in tumoral and matched non-tumoral tissues was carried out in order to investigate the clonal profile and the pathogenic role of the identified variants.
Results: Filtering for rare variants with CADD>25 and potentially damaging effect, we identified rare/private germline deleterious variants in 11 cancer-associated genes, none of which, except one, shared with the healthy sib, pinpointing to a "private" oligogenic germline signature. Noteworthy, among these, two mutated genes, namely ACACA and DEPTOR, turned to be potential targets for therapy because related to known drivers, such as BRCA1 and EGFR.
Conclusions: In the era of precision medicine, this report emphasizes the importance of an "omic" approach to uncover oligogenic germline signature underlying cancer development and to identify suitable therapeutic targets as well.
PMID: 28546520 [PubMed - as supplied by publisher]
Increased Survival and Partly Preserved Cognition in a Patient With ACO2-Related Disease Secondary to a Novel Variant.
Increased Survival and Partly Preserved Cognition in a Patient With ACO2-Related Disease Secondary to a Novel Variant.
J Child Neurol. 2017 Jan 01;:883073817711527
Authors: Srivastava S, Gubbels CS, Dies K, Fulton A, Yu T, Sahin M
Abstract
ACO2 encodes aconitase 2, catalyzing the second step of the tricarboxylic acid. To date, there are only 6 reported families with 5 unique ACO2 mutations. Affected individuals can develop intellectual disability, epilepsy, brain atrophy, hypotonia, ataxia, optic atrophy, and retinal degeneration. Here, we report an 18-year-old boy with a novel ACO2 variant discovered on whole-exome sequencing. He presented with childhood-onset ataxia, impaired self-help skills comparable to severe-profound intellectual disability, intractable epilepsy, cerebellar atrophy, peripheral neuropathy, optic atrophy, and pigmentary retinopathy. His variant is the sixth unique ACO2 mutation. In addition, compared to mild cases (isolated optic atrophy) and severe cases (infantile death), our patient may be moderately affected, evident by increased survival and some preserved cognition (ability to speak full sentences and follow commands), which is a novel presentation. This case expands the disease spectrum to include increased survival with partly spared cognition.
PMID: 28545339 [PubMed - as supplied by publisher]
Risk factors and mechanisms contributing to TKI-induced vascular events in patients with CML.
Risk factors and mechanisms contributing to TKI-induced vascular events in patients with CML.
Leuk Res. 2017 May 12;59:47-54
Authors: Valent P, Hadzijusufovic E, Hoermann G, Füreder W, Schernthaner GH, Sperr WR, Kirchmair R, Wolf D
Abstract
Vascular adverse events (VAE) are an emerging problem in patients with chronic myeloid leukemia (CML) receiving second-generation BCR-ABL1 tyrosine kinase inhibitors (TKI). Relevant VAE comprise peripheral, cerebral, and coronary artery changes in patients receiving nilotinib, venous and arterial occlusive events during ponatinib therapy, and pulmonary hypertension in patients receiving dasatinib. Although each TKI binds to a unique profile of molecular targets in leukemic cells and vascular cells, the exact etiology of drug-induced vasculopathies remains uncertain. Recent data suggest that predisposing molecular factors, pre-existing cardiovascular risk factors as well as certain comorbidities contribute to the etiology of VAE in these patients. In addition, direct effects of these TKI on vascular endothelial cells have been demonstrated and are considered to contribute essentially to VAE evolution. In the current article, we discuss mechanisms underlying the occurrence of VAE in TKI-treated patients with CML, with special emphasis on vascular and perivascular target cells and involved molecular (vascular) targets of VAE-triggering TKI. In addition, we discuss optimal patient selection and drug selection through which the risk of occurrence of cardiovascular events can hopefully be minimized while maintaining optimal anti-leukemic effects in CML, thereby following the principles of personalized medicine.
PMID: 28549238 [PubMed - as supplied by publisher]
[Prevalence of potential drug-drug interactions involving antiretroviral drugs in Buenos Aires, Argentina].
[Prevalence of potential drug-drug interactions involving antiretroviral drugs in Buenos Aires, Argentina].
Rev Chilena Infectol. 2016 Oct;33(Suppl 1):54-59
Authors: Córdova E, Porteiro N, Loiza E, Mingrone H
Abstract
INTRODUCTION: Antiretroviral agents (ARVs) have a high potential for drug interactions. However, the prevalence and risk factors for clinically significant drug-drug interactions (CSDDIs) with ARVs from Latin American countries is unknown.
AIM: To evaluate the prevalence and risk factors for CSDDIs in HIV outpatients attending at two centers in Buenos Aires, Argentina.
METHODS: Descriptive cross-sectional study (september to november 2012). HIV-1 infected patients under ARV treatment at the time of the study were randomly assessed for concomitant medication. CSDDIs were screened using the University of Liverpool Drug Interactions Program (www.hiv-druginteractions.org).
RESULTS: A total of 217 patients were included. Male sex: 64% (CI 95: 57-70). Median age (IQR): 41 (36-48). Presence of comorbidities: 19%. ARV regimen: NNRTI-based: 48%, PI-based: 50% and NNRTI plus PI: 2%. Median of CD4 T-cell count (IQR): 402 cells/mL (235-588). Viral load < 50 copies/mL: 78%. Overall, 64% (CI 95: 57-70) of patients had > 1 co-medication of whom a 49% had at least one CSDDI. Two patients had a CSDDI between ARVs. The most frequent co-medications observed were antimicrobial (40%), cardiovascular (25%) and gastrointestinal agents (22%). In the multivariate analysis the number of co-medications and use of CNS agents were associated with the presence of CSDDIs.
CONCLUSIONS: Co-medications and CSDDIs were common in our setting. In this context, training of HIV physicians in drug interactions is of major importance for adequate management of these patients.
PMID: 28453027 [PubMed - indexed for MEDLINE]
[The clinical relevance of drug interactions in patients with human immunodeficiency virus infection: update 2009-2014].
[The clinical relevance of drug interactions in patients with human immunodeficiency virus infection: update 2009-2014].
Rev Chilena Infectol. 2016 Oct;33(Suppl 1):36-53
Authors: Giraldo NA, Amariles P, Pino Marín DE, Faus MJ
Abstract
OBJECTIVE: To update information about drug interactions in patients with HIV/AIDS.
METHODS: Comprehensive literature review in MEDLINE/PubMed database from May of 2009 to December of 2014, using the Mesh terms: Anti-retroviral agents and drug interactions or herb-drug interactions or food-drug interactions. Publications with drug interactions in humans, in English or Spanish, and with full text were retrieved. Additionally, citation lists from identified articles were reviewed. The study inclusion was assessed by three independent researchers and by consensus among them when was necessary. Clinical relevance of drug interaction was grouped into four levels according to seriously and probability of occurrence.
RESULTS: Global, 546 different references were retrieved and 243 were selected. In addition 11 further manuscripts were identified in the references of the included articles. Overall, 935 pairs of drug interactions were identified, 95.7% pharmacokinetic (823 by enzyme induction or inhibition and 67 by changes in bioavailability). Of the 935 pairs of drug interactions, 402(43%) were classified as levels 1 or 2.
CONCLUSIONS: The most clinically relevant antiretroviral drug interactions are due to pharmacokinetic mechanism, mainly induction or enzyme inhibition, according to previous reviews, the protease inhibitors remain as the antiretrovirals with the highest number of clinical relevant interactions.
PMID: 28453026 [PubMed - indexed for MEDLINE]
Can Disproportionality Analysis of Post-marketing Case Reports be Used for Comparison of Drug Safety Profiles?
Can Disproportionality Analysis of Post-marketing Case Reports be Used for Comparison of Drug Safety Profiles?
Clin Drug Investig. 2017 May;37(5):415-422
Authors: Michel C, Scosyrev E, Petrin M, Schmouder R
Abstract
Clinical trials usually do not have the power to detect rare adverse drug reactions. Spontaneous adverse reaction reports as for example available in post-marketing safety databases such as the FDA Adverse Event Reporting System (FAERS) are therefore a valuable source of information to detect new safety signals early. To screen such large data-volumes for safety signals, data-mining algorithms based on the concept of disproportionality have been developed. Because disproportionality analysis is based on spontaneous reports submitted for a large number of drugs and adverse event types, one might consider using these data to compare safety profiles across drugs. In fact, recent publications have promoted this practice, claiming to provide guidance on treatment decisions to healthcare decision makers. In this article we investigate the validity of this approach. We argue that disproportionality cannot be used for comparative drug safety analysis beyond basic hypothesis generation because measures of disproportionality are: (1) missing the incidence denominators, (2) subject to severe reporting bias, and (3) not adjusted for confounding. Hypotheses generated by disproportionality analyses must be investigated by more robust methods before they can be allowed to influence clinical decisions.
PMID: 28224371 [PubMed - indexed for MEDLINE]
Longitudinal assessment of nutritional risk in patients under chemo or radiotherapy.
Longitudinal assessment of nutritional risk in patients under chemo or radiotherapy.
Rev Assoc Med Bras (1992). 2016 Oct;62(7):659-663
Authors: Mastelaro I, Pupin MP, Ribeiro SM, Oliveira HF, Peria FM, Cunha SF
Abstract
Objective:: To compare nutritional risk in adult patients undergoing chemotherapy and radiotherapy in the beginning, middle, and end of oncologic treatment.
Method:: This prospective, comparative study included 83 adult patients, 44 undergoing chemotherapy (CT group) and 39 undergoing radiotherapy (RT group) at an oncology treatment center. Nutritional risk was determined by NRS-2002 in the beginning, middle, and end of therapy. Statistical analysis was performed using Statistica 8.0 software.
Results:: No differences in food intake or body mass index were observed between the CT (24.6±4.8 kg/m²) and RT groups (25.0±5.9 kg/m², p=0.75). Weight loss in the preceding 3 months was detected in 56.8% of CT group and 38.5% of RT group (p=0.09). The weight loss percentage compared with the usual weight within 3 months was greater (p<0.001) in the CT (11.4±6.5%) than in the RT group (3.9±6.8%). In the beginning of treatment, we observed high percentages of patients at moderate (18.2 vs. 15.4%, p=0.73) and high nutritional risk (61.4 vs. 48.7%, p=0.25), with no statistical difference between the CT and RT groups, respectively. During therapy, the nutritional risk remained unaltered in both groups. In the end of therapy, the majority of patients were at moderate (18.2 vs. 12.8%, p=0.50) or severe nutritional risk (50.0 vs. 51.3%, p=0.91), in the CT and RT groups, respectively, regardless of the type of oncologic treatment.
Conclusion:: The high prevalence of patients at moderate or high nutritional risk in the beginning of treatment indicates the need for an early and continuous follow-up of the nutritional status of patients undergoing oncologic treatment.
PMID: 27925046 [PubMed - indexed for MEDLINE]
Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study.
Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study.
PLoS Med. 2016 Aug;13(8):e1002058
Authors: Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DP
Abstract
BACKGROUND: There is limited, poorly characterized information about adverse events occurring during maintenance treatment of bipolar disorder. We aimed to determine adverse event rates during treatment with lithium, valproate, olanzapine, and quetiapine.
METHODS AND FINDINGS: We conducted a propensity score adjusted cohort study using nationally representative United Kingdom electronic health records from January 1, 1995, until December 31, 2013. We included patients who had a diagnosis of bipolar disorder and were prescribed lithium (n = 2148), valproate (n = 1670), olanzapine (n = 1477), or quetiapine (n = 1376) as maintenance mood stabilizer treatment. Adverse outcomes were chronic kidney disease, thyroid disease, hypercalcemia, weight gain, hypertension, type 2 diabetes mellitus, cardiovascular disease, and hepatotoxicity. The propensity score included important demographic, physical health, and mental health predictors of drug treatment allocation. The median duration of drug treatment was 1.48 y (interquartile range 0.64-3.43). Compared to patients prescribed lithium, those taking valproate, olanzapine, and quetiapine had reduced rates of chronic kidney disease stage 3 or more severe, following adjustment for propensity score, age, and calendar year, and accounting for clustering by primary care practice (valproate hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.45-0.69; p < 0.001, olanzapine HR 0.57; 95% CI 0.45-0.71; p < 0.001, quetiapine HR 0.62; 95% CI 0.47-0.80; p < 0.001). Hypothyroidism was reduced in those taking valproate (HR 0.60; 95% CI 0.40-0.89; p = 0.012) and olanzapine (HR 0.48; 95% CI 0.29-0.77; p = 0.003), compared to those taking lithium. Rates of new onset hyperthyroidism (valproate HR 0.24; 95% CI 0.09-0.61; p = 0.003, olanzapine HR 0.31; 95% CI 0.13-0.73; p = 0.007) and hypercalcemia (valproate HR 0.25; 95% CI 0.10-0.60; p = 0.002, olanzapine HR 0.32; 95% CI 0.14-0.76; p = 0.008, quetiapine HR 0.23; 95% CI 0.07-0.73; p = 0.013) were also reduced relative to lithium. However, rates of greater than 15% weight gain on valproate, olanzapine, and quetiapine were higher (valproate HR 1.62; 95% CI 1.31-2.01; p < 0.001, olanzapine HR 1.84; 95% CI 1.47-2.30; p < 0.001, quetiapine HR 1.67; 95% CI 1.24-2.20; p < 0.001) than in individuals prescribed lithium, as were rates of hypertension in the olanzapine treated group (HR 1.41, 95% CI 1.06-1.87; p = 0.017). We found no significant difference in rates of chronic kidney disease stage 4 or more severe, type 2 diabetes mellitus, cardiovascular disease, or hepatotoxicity. Despite estimates being robust following sensitivity analyses, limitations include the potential for residual confounding and ascertainment bias and an inability to examine dosage effects.
CONCLUSIONS: Lithium use is associated with more renal and endocrine adverse events but less weight gain than commonly used alternative mood stabilizers. Risks need to be offset with the effectiveness and anti-suicidal benefits of lithium and the potential metabolic side effects of alternative treatment options.
PMID: 27483368 [PubMed - indexed for MEDLINE]
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Grants for Early Medical/Surgical Specialists' Transition to Aging Research (GEMSSTAR) (R03)
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