Improved Growth Patterns in Cystic Fibrosis Mice after Loss of Histone Deacetylase 6.

Sci Rep. 2017 Jun 16;7(1):3676

Authors: Rymut SM, Corey DA, Valerio DM, Erokwu BO, Flask CA, Kelley TJ, Hodges CA

Abstract
Growth failure in cystic fibrosis (CF) patients has been well-documented and shown to correlate with poorer disease outcomes. This observation is also true in CF animal models, including mouse, pig, rat, and ferret. The etiology underlying growth deficits is unknown, and our previous work demonstrated reduced tubulin acetylation in CF cell models and tissue that is correctable by inhibition of histone deacetylase-6 (HDAC6). Here, we hypothesize that loss of HDAC6 will improve growth phenotype in a CF mouse model. Hdac6 knockout mice were crossed with F508del (CF) mice to generate F508del/Hdac6 (CF/HDA) mice. Growth, fat deposits, survival, and bioelectric measurements were analyzed. CF/HDA mice displayed improvements in length and weight with no correction of CFTR function. Mechanistically, Igf1 levels likely account for increased length and improvements in fertility. Weight gain is attributed to increased fat deposits potentially mediated by increased adipocyte differentiation. CF-related growth deficits can be improved via inhibition of HDAC6, further implicating it as a potential therapeutic target for CF.

PMID: 28623308 [PubMed - in process]

High level of β-(1,3)-d-glucan antigenaemia in cystic fibrosis in the absence of invasive fungal disease.

Diagn Microbiol Infect Dis. 2017 May 18;:

Authors: Rautemaa V, Green HD, Jones AM, Rautemaa-Richardson R

Abstract
β-(1,3)-d-glucan (BDG) is used to rule out invasive fungal disease (IFD) but its usefulness in cystic fibrosis (CF) has not been evaluated. We measured serum BDG in CF patients with no clinical suspicion of IFD. Samples from 46 adult CF patients during a stable period and during pulmonary exacerbation were tested. The association of BDG with clinical variables was analyzed. Three hundred and three non-CF patients with suspected IFD were used as comparators. Both samples were negative in 52% of CF patients, whereas 67% of comparators had only negative results (P=0.08). CF patients with pancreatic insufficiency and CF-related diabetes had fewer negative results (P<0.05 for both). Negative results were more common in older CF patients (P<0.05). Use of antibiotics, presence of fungi in sputum and CF liver disease did not impact BDG levels. In conclusion, patients with CF experience significant BDG antigenaemia in the absence of IFD.

PMID: 28622948 [PubMed - as supplied by publisher]

Effect of acute predation with bacteriophage on intermicrobial aggression by Pseudomonas aeruginosa.

PLoS One. 2017;12(6):e0179659

Authors: Secor PR, Sass G, Nazik H, Stevens DA

Abstract
In persons with structural lung disease, particularly those with cystic fibrosis (CF), chronic airway infections cause progressive loss of lung function. CF airways can be colonized by a variety of microorganisms; the most frequently encountered bacterial and fungal pathogens are Pseudomonas aeruginosa and Aspergillus fumigatus, respectively. Co-infection with P. aeruginosa and A. fumigatus often results in a more rapid loss of lung function, indicating that interactions between these pathogens affect infection pathogenesis. There has been renewed interest in the use of viruses (bacteriophage, mycoviruses) as alternatives to antibiotics to treat these infections. In previous work, we found that filamentous Pf bacteriophage produced by P. aeruginosa directly inhibited the metabolic activity of A. fumigatus by binding to and sequestering iron. In the current study, we further examined how filamentous Pf bacteriophage affected interactions between P. aeruginosa and A. fumigatus. Here, we report that the antifungal properties of supernatants collected from P. aeruginosa cultures infected with Pf bacteriophage were substantially less inhibitory towards A. fumigatus biofilms. In particular, we found that acute infection of P. aeruginosa by Pf bacteriophage inhibited the production of the virulence factor pyoverdine. Our results raise the possibility that the reduced production of antimicrobials by P. aeruginosa infected by Pf bacteriophage may promote conditions in CF airways that allow co-infection with A. fumigatus to occur, exacerbating disease severity. Our results also highlight the importance of considering how the use of bacteriophage as therapeutic agents could affect the behavior and composition of polymicrobial communities colonizing sites of chronic infection.

PMID: 28622385 [PubMed - in process]

Increased immunogenicity and protective efficacy of the P. aeruginosa vaccine in mice using an alum and de-O-acylated lipooligosaccharide adjuvant system.

J Microbiol Biotechnol. 2017 Jun 16;:

Authors: Ryu JI, Wui SR, Ko A, Lee YJ, Do HTT, Kim HJ, Rhee IM, Park SA, Kim KS, Cho YJ, Lee NG

Abstract
Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen that commonly causes fatal infections in cystic fibrosis and burn patients as well as in patients who are hospitalized or have impaired immune systems. P. aeruginosa infections are difficult to treat due to the high resistance of the pathogen to conventional antibiotics. Despite several efforts, no effective prophylactic vaccines against P. aeruginosa are currently available. In this study, we investigated the activity of the CIA06 adjuvant system, which is comprised of alum and de-O-acylated lipooligosaccharide, on a P. aeruginosa outer membrane protein (OMP) antigen vaccine in mice. The results indicated that CIA06 significantly increased the antigen-specific IgG titers and opsonophagocytic activity of immune sera against P. aeruginosa. In addition, the antibodies induced by the CIA06-adjuvanted vaccine exhibited higher cross-reactivity with heterologous P. aeruginosa strains. Finally, mice immunized with the CIA06-adjuvanted vaccine were effectively protected from lethal P. aeruginosa challenge. Based on these data, we suggest that the CIA06 adjuvant system might be used to promote the immunogenicity and protective efficacy of the P. aeruginosa OMP vaccine.

PMID: 28621112 [PubMed - as supplied by publisher]

A novel homozygous complex deletion in CFTR caused cystic fibrosis in a Chinese patient.

Mol Genet Genomics. 2017 Jun 15;:

Authors: Liu K, Liu Y, Li X, Xu KF, Tian X, Zhang X

Abstract
Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians, but is considered to be a very rare disease in Chinese population. Here, we present an 11-year-old Chinese CF patient with disseminated bronchiectasis and salty sweat, for whom exon sequencing followed by multiplex ligation-dependent probe amplification analysis of the CFTR gene was applied for mutation screening. A homozygous deletion involving exon 20 of CFTR was observed in the patient's genome. Molecular characterization of the breakpoints indicated that both alleles of this locus had an identical novel complex rearrangement (c.3140-454_c.3367+249del931ins13, p.R1048_G1123del), leading to an in-frame removal of 76 amino acid residues in the second transmembrane domains of the CFTR protein. Although a same haplotype containing this complex rearrangement was observed on both of the maternal and paternal alleles, the parents denied any blood relationship as far as they know. Genome-wide homozygosity mapping was performed through SNP microarray and only a single homozygous interval of ~14.1 Mb at chromosome 7 containing the CFTR gene was observed, indicating the possible origin of the deletion from a common ancestor many generations ago. This study expands the mutation spectrum of CFTR in patients of Chinese origin and further emphasizes the necessity of MLPA analysis in mutation screening for CF patients.

PMID: 28620757 [PubMed - as supplied by publisher]

Postnatal Airway Growth in Cystic Fibrosis Piglets.

J Appl Physiol (1985). 2017 Jun 15;:jap.00263.2017

Authors: Adam RJ, Abou Alaiwa MH, Bouzek DC, Cook DP, Gansemer ND, Taft PJ, Powers LS, Stroik MR, Hoegger MJ, McMenimen JD, Hoffman EA, Zabner J, Welsh MJ, Meyerholz DK, Stoltz DA

Abstract
Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel cause cystic fibrosis (CF). The leading cause of death in the CF population is lung disease. Increasing evidence suggests that in utero airway development is CFTR-dependent and that developmental abnormalities may contribute to CF lung disease. However, relatively little is known of postnatal CF airway growth, largely because such studies are limited in people. Therefore, we examined airway growth and lung volume in a porcine model of CF. We hypothesized that CF pigs would have abnormal postnatal airway growth. To test this hypothesis, we performed CT-based airway and lung volume measurements in three-week-old non-CF and CF pigs. We found that three-week-old CF pigs had tracheas of reduced caliber and irregular shape. Their bronchial lumens were reduced in size proximally but not distally, were irregularly shaped, and had reduced distensibility. Our data suggest that lack of CFTR results in aberrant postnatal airway growth and development, which could contribute to CF lung disease pathogenesis.

PMID: 28620056 [PubMed - as supplied by publisher]

Committee Opinion No. 691: Carrier Screening for Genetic Conditions.

Obstet Gynecol. 2017 03;129(3):e41-e55

Authors: Committee on Genetics

Abstract
Carrier screening is a term used to describe genetic testing that is performed on an individual who does not have any overt phenotype for a genetic disorder but may have one variant allele within a gene(s) associated with a diagnosis. Information about carrier screening should be provided to every pregnant woman. Carrier screening and counseling ideally should be performed before pregnancy because this enables couples to learn about their reproductive risk and consider the most complete range of reproductive options. A patient may decline any or all screening. When an individual is found to be a carrier for a genetic condition, his or her relatives are at risk of carrying the same mutation. The patient should be encouraged to inform his or her relatives of the risk and the availability of carrier screening. If an individual is found to be a carrier for a specific condition, the patient's reproductive partner should be offered testing in order to receive informed genetic counseling about potential reproductive outcomes. If both partners are found to be carriers of a genetic condition, genetic counseling should be offered. What follows is a detailed discussion of some of the more common genetic conditions for which carrier screening is recommended in at least some segments of the population.

PMID: 28225426 [PubMed - indexed for MEDLINE]

Early-onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman-Steiner and Roifman syndromes.

Sci Rep. 2017 Jun 16;7(1):3702

Authors: Bogaert DJ, Dullaers M, Kuehn HS, Leroy BP, Niemela JE, De Wilde H, De Schryver S, De Bruyne M, Coppieters F, Lambrecht BN, De Baets F, Rosenzweig SD, De Baere E, Haerynck F

Abstract
Syndromic primary immunodeficiencies are rare genetic disorders that affect both the immune system and other organ systems. More often, the immune defect is not the major clinical problem and is sometimes only recognized after a diagnosis has been made based on extra-immunological abnormalities. Here, we report two sibling pairs with syndromic primary immunodeficiencies that exceptionally presented with a phenotype resembling early-onset common variable immunodeficiency, while extra-immunological characteristics were not apparent at that time. Additional features not typically associated with common variable immunodeficiency were diagnosed only later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. With this study, we underline the importance of an early-stage and thorough genetic assessment in paediatric patients with a common variable immunodeficiency phenotype, to establish a conclusive diagnosis and guide patient management. In addition, this study extends the mutational and immunophenotypical spectrum of Wiedemann-Steiner and Roifman syndromes and highlights potential directions for future pathophysiological research.

PMID: 28623346 [PubMed - in process]

Commentary on "Inherited DNA-repair gene mutations in men with metastatic prostate cancer". Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS. N Engl J Med. 2016;375(5):443-53.

Urol Oncol. 2017 Jun 13;:

Authors: Freedland SJ, Aronson WJ

Abstract
BACKGROUND: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established.
METHODS: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes.
RESULTS: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001).
CONCLUSIONS: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer.

PMID: 28623070 [PubMed - as supplied by publisher]

A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca(2+) signal patterns.

J Neurol. 2017 Jun 15;:

Authors: Casey JP, Hirouchi T, Hisatsune C, Lynch B, Murphy R, Dunne AM, Miyamoto A, Ennis S, van der Spek N, O'Hici B, Mikoshiba K, Lynch SA

Abstract
We report three affected members, a mother and her two children, of a non-consanguineous Irish family who presented with a suspected autosomal dominant spinocerebellar ataxia characterized by early motor delay, poor coordination, gait ataxia, and dysarthria. Whole exome sequencing identified a novel missense variant (c.106C>T; p.[Arg36Cys]) in the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor gene (ITPR1) as the cause of the disorder, resulting in a molecular diagnosis of spinocerebellar ataxia type 29. In the absence of grandparental DNA, microsatellite genotyping of healthy family members was used to confirm the de novo status of the ITPR1 variant in the affected mother, which supported pathogenicity. The Arg36Cys variant exhibited a significantly higher IP3-binding affinity than wild-type (WT) ITPR1 and drastically changed the property of the intracellular Ca(2+) signal from a transient to a sigmoidal pattern, supporting a gain-of-function disease mechanism. To date, ITPR1 mutation has been associated with a loss-of-function effect, likely due to reduced Ca(2+) release. This is the first gain-of-function mechanism to be associated with ITPR1-related SCA29, providing novel insights into how enhanced Ca(2+) release can also contribute to the pathogenesis of this neurological disorder.

PMID: 28620721 [PubMed - as supplied by publisher]

A Path to Implement Precision Child Health Cardiovascular Medicine.

Front Cardiovasc Med. 2017;4:36

Authors: Touma M, Reemtsen B, Halnon N, Alejos J, Finn JP, Nelson SF, Wang Y

Abstract
Congenital heart defects (CHDs) affect approximately 1% of live births and are a major source of childhood morbidity and mortality even in countries with advanced healthcare systems. Along with phenotypic heterogeneity, the underlying etiology of CHDs is multifactorial, involving genetic, epigenetic, and/or environmental contributors. Clear dissection of the underlying mechanism is a powerful step to establish individualized therapies. However, the majority of CHDs are yet to be clearly diagnosed for the underlying genetic and environmental factors, and even less with effective therapies. Although the survival rate for CHDs is steadily improving, there is still a significant unmet need for refining diagnostic precision and establishing targeted therapies to optimize life quality and to minimize future complications. In particular, proper identification of disease associated genetic variants in humans has been challenging, and this greatly impedes our ability to delineate gene-environment interactions that contribute to the pathogenesis of CHDs. Implementing a systematic multileveled approach can establish a continuum from phenotypic characterization in the clinic to molecular dissection using combined next-generation sequencing platforms and validation studies in suitable models at the bench. Key elements necessary to advance the field are: first, proper delineation of the phenotypic spectrum of CHDs; second, defining the molecular genotype/phenotype by combining whole-exome sequencing and transcriptome analysis; third, integration of phenotypic, genotypic, and molecular datasets to identify molecular network contributing to CHDs; fourth, generation of relevant disease models and multileveled experimental investigations. In order to achieve all these goals, access to high-quality biological specimens from well-defined patient cohorts is a crucial step. Therefore, establishing a CHD BioCore is an essential infrastructure and a critical step on the path toward precision child health cardiovascular medicine.

PMID: 28620608 [PubMed - in process]

The Andalusian Bipolar Family (ABiF) Study: Protocol and sample description.

Rev Psiquiatr Salud Ment. 2017 Jun 12;:

Authors: Guzman-Parra J, Rivas F, Strohmaier J, Forstner A, Streit F, Auburger G, Propping P, Orozco-Diaz G, González MJ, Gil-Flores S, Cabaleiro-Fabeiro FJ, Del Río-Noriega F, Perez-Perez F, Haro-González J, de Diego-Otero Y, Romero-Sanchiz P, Moreno-Küstner B, Cichon S, Nöthen MM, Rietschel M, Mayoral F

Abstract
INTRODUCTION: Here, we present the first description of the Andalusian Bipolar Family (ABiF) Study. This longitudinal investigation of families from Andalusia, Spain commenced in 1997 with the aim of elucidating the molecular genetic causes of bipolar affective disorder. The cohort has since contributed to a number of key genetic findings, as reported in international journals. However, insight into the genetic underpinnings of the disorder in these families remains limited.
METHOD: In the initial 1997-2003 study phase, 100 multiplex bipolar disorder and other mood disorder families were recruited. The ongoing second phase of the project commenced in 2013, and involves follow-up of a subgroup of the originally recruited families. The aim of the follow-up investigation is to generate: i) longitudinal clinical data; ii) results from detailed neuropsychological assessments; and iii) a more extensive collection of biomaterials for future molecular biological studies.
RESULTS: The ABiF Study will thus generate a valuable resource for future investigations into the aetiology of bipolar affective disorder; in particular the causes of high disease loading within multiply affected families.
DISCUSSION: We discuss the value of this approach in terms of new technologies for the identification of high-penetrance genetic factors. These new technologies include exome and whole genome sequencing, and the use of induced pluripotent stem cells or model organisms to determine functional consequences.

PMID: 28619597 [PubMed - as supplied by publisher]

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis.

Haematologica. 2016 Oct;101(10):1180-1189

Authors: Walne AJ, Collopy L, Cardoso S, Ellison A, Plagnol V, Albayrak C, Albayrak D, Kilic SS, Patıroglu T, Akar H, Godfrey K, Carter T, Marafie M, Vora A, Sundin M, Vulliamy T, Tummala H, Dokal I

Abstract
Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.

PMID: 27612988 [PubMed - indexed for MEDLINE]

Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families.

Eur J Hum Genet. 2016 Oct;24(10):1430-5

Authors: Issa YA, Kamal L, Rayyan AA, Dweik D, Pierce S, Lee MK, King MC, Walsh T, Kanaan M

Abstract
Tooth development is controlled by the same processes that regulate formation of other ectodermal structures. Mutations in the genes underlying these processes may cause ectodermal dysplasia, including severe absence of primary or permanent teeth. Four consanguineous Palestinian families presented with oligodontia and hair and skin features of ectodermal dysplasia. Appearance of ectodermal dysplasia was consistent with autosomal recessive inheritance. Exome sequencing followed by genotyping of 56 informative relatives in the 4 families suggests that the phenotype is due to homozygosity for KREMEN1 p.F209S (c.626 T>C) on chromosome 22 at g.29,521,399 (hg19). The variant occurs in the highly conserved extracellular WSC domain of KREMEN1, which is known to be a high affinity receptor of Dickkopf-1, a component of the Dickkopf-Kremen-LRP6 complex, and a potent regulator of Wnt signaling. The Wnt signaling pathway is critical to development of ectodermal structures. Mutations in WNT10A, LRP6, EDA, and other genes in this pathway lead to tooth agenesis with or without other ectodermal anomalies. Our results implicate KREMEN1 for the first time in a human disorder and provide additional details on the role of the Wnt signaling in ectodermal and dental development.

PMID: 27049303 [PubMed - indexed for MEDLINE]

Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective Janus kinase 1 inhibitor, after short-term treatment of rheumatoid arthritis: Results of two randomized Phase IIA trials.

Arthritis Rheumatol. 2017 Jun 16;:

Authors: Vanhoutte F, Mazur M, Voloshyn O, Stanislavchuk M, Van der Aa A, Namour F, Galien R, Meuleners L, van 't Klooster G

Abstract
OBJECTIVE: Janus kinase (JAK) inhibitors have shown efficacy in rheumatoid arthritis (RA). We hypothesized that selective inhibition of JAK1 would combine good efficacy with a differentiated safety profile versus less selective JAK inhibitors.
METHODS: In two 4-week exploratory, double-blind, placebo-controlled Phase IIA trials, 127 RA patients with insufficient response to methotrexate received filgotinib (GLPG0634, GS-6034) oral capsules (twice-daily 100 mg, or once-daily 30, 75, 150, 200, or 300 mg) or placebo, added on to a stable regimen of methotrexate, to evaluate safety, efficacy, pharmacokinetics and pharmacodynamics of filgotinib. The primary endpoint was the American College of Rheumatology 20% improvement (ACR20) response rate at Week 4.
RESULTS: Filgotinib (75-300 mg) treatment met the primary endpoint and showed early onset of efficacy. ACR20 response rates progressively increased to Week 4, and DAS28 [CRP] decreased. Marked and sustained improvements in serum CRP and other pharmacodynamic markers were observed. The pharmacokinetic exposure increased dose proportionally within the 30-300 mg dose range. Early side effects observed with other less selective JAK inhibitors were not observed, such as no worsening of anemia (JAK2 related), no effects on liver transaminases and no increase in LDL/cholesterol. A limited decrease in neutrophils, but no neutropenia, was consistent with immunomodulatory effects through JAK1 inhibition. There were no infections. Overall, filgotinib was well tolerated with study drug-related events mild to moderate and transient on therapy, the most common being nausea.
CONCLUSION: Selective inhibition of JAK1 by filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies. This article is protected by copyright. All rights reserved.

PMID: 28622463 [PubMed - as supplied by publisher]

Antipsychotic Use Among Adult Outpatients and Venous Thromboembolic Disease: A Retrospective Cohort Study.

J Clin Psychopharmacol. 2017 Jun 15;:

Authors: Ferraris A, Szmulewicz AG, Vazquez FJ, Vollmer WM, Angriman F

Abstract
BACKGROUND: Treatment with antipsychotic (AP) agents is associated with incident thromboembolic events. However, the underpinnings of this association remain unknown. We sought to evaluate the effect of AP agents-categorized by their metabolic/sedative and hyperprolactinemia adverse effect profile-on the risk of venous thromboembolic disease during long-term follow-up.
METHODS: A retrospective cohort study of adult patients initiating AP treatment for the first time was conducted. Primary outcome was defined as the time to venous thromboembolism (VTE) (either deep venous thrombosis or acute pulmonary embolism). Antipsychotic agents were categorized by their risk (high vs low) of either drug-induced (a) sedation/metabolic adverse event or (b) hyperprolactinemia. We used a propensity score-adjusted Cox proportional hazards model to control for confounding.
FINDINGS: One thousand eight patients (mean age, 72.4 y) were followed for a median of 36 months. Incident VTE occurred in 6.25% of patients, corresponding to an incidence rate of 184 cases per 10,000 person-years. We found no difference in the hazard of VTE during follow-up between high- and low-risk groups (hazard ratio, 1.23 [95% confidence interval, 0.74-2.04] for drug-induced sedation/metabolic adverse event risk categories, and hazard ratio 0.81 [95% confidence interval, 0.50-1.35] for high versus low hyperprolactinemia risk).
CONCLUSIONS: These results suggest that the risk of thromboembolic events in older adults who started AP treatment for the first time does not seem to be related to these drugs' risk of either sedation/metabolic adverse events or hyperprolactinemia. However, VTE remains a common problem in this subgroup of patients.

PMID: 28622161 [PubMed - as supplied by publisher]

Real-World Efficacy of Daclatasvir and Sofosbuvir, With and Without Ribavirin, in HIV/HCV Coinfected Patients With Advanced Liver Disease in a French Early Access Cohort.

J Acquir Immune Defic Syndr. 2017 May 01;75(1):97-107

Authors: Lacombe K, Fontaine H, Dhiver C, Metivier S, Rosenthal E, Antonini T, Valantin MA, Miailhes P, Harent S, Batisse D, Pageaux GP, Chas J, Aumaitre H, Dominguez S, Allegre T, Lafeuillade A, Billaud E, De Truchis P, Perre P, Leroy V, De Ledinghen V, Sogni P, Dabis F, Zhao Y, Filipovics A, Fedchuk L, Akremi R, Bennai Y, Salmon Ceron D

Abstract
BACKGROUND: Efficacious, well-tolerated, direct antiviral agents have drastically changed the prognosis of hepatitis C virus (HCV) disease, but real-world data for oral treatments are limited in key populations such as HIV/HCV coinfection with advanced liver disease. Daclatasvir (DCV) efficacy and safety was assessed in the French "Autorisation Temporaire d'Utilisation" (ATU) program, providing DCV ahead of market authorization to patients with advanced HCV disease without other treatment options.
METHODS: This was a subanalysis of HIV/HCV coinfected ATU patients treated with DCV plus sofosbuvir (SOF). Recommended duration was 24 weeks; addition of ribavirin (RBV) and/or shorter treatment was at the physician's discretion. The primary efficacy analysis was sustained virologic response at posttreatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting.
RESULTS: The efficacy population (N = 407) was mostly cirrhotic (72%, of whom 18% were decompensated), HCV treatment-experienced (82%), and infected with genotypes 1 (69%), 3 (12%), or 4 (19%). Median CD4 was 555 cells/mm; 95% had HIV RNA <50 copies/mL. Most (74%) were treated for 24 weeks; 14% received RBV. SVR12 was 92% overall (95% confidence interval: 88.6% to 94.0%); 90% (86.4% to 93.2%) in patients with cirrhosis; 95% (88.9% to 97.5%) in patients without cirrhosis. SVR12 was consistent across HCV genotypes and antiretroviral regimens. Among 617 patients with safety data, 7 discontinued for an adverse event and 10 died.
CONCLUSIONS: DCV+SOF±RBV achieved high SVR12 and was well tolerated in this large real-world cohort of HIV/HCV coinfected patients with advanced liver disease.

PMID: 28272163 [PubMed - indexed for MEDLINE]

Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.

J Acquir Immune Defic Syndr. 2017 May 01;75(1):61-66

Authors: Gallant JE, Thompson M, DeJesus E, Voskuhl GW, Wei X, Zhang H, White K, Cheng A, Quirk E, Martin H

Abstract
OBJECTIVE: To evaluate antiviral activity, safety, and pharmacokinetics of short-term monotherapy with bictegravir (BIC), a novel, potent HIV integrase strand transfer inhibitor (INSTI).
DESIGN: Phase 1b, randomized, double-blinded, adaptive, sequential cohort, placebo-controlled study.
METHODS: HIV-infected adults not taking antiretroviral therapy were randomized to receive BIC (5, 25, 50, or 100 mg) or placebo once daily for 10 days. Primary endpoint was time-weighted average change from baseline to day 11 (DAVG11) for plasma HIV-1 RNA. HIV-1 RNA, adverse events (AEs), and laboratory assessments were evaluated through day 17.
RESULTS: Twenty participants were enrolled (n = 4/group). Mean DAVG11 ranged from -0.92 to -1.61 across BIC doses versus -0.01 for placebo. Significant reductions in plasma HIV-1 RNA from baseline at day 11 were observed for all BIC doses compared with placebo (P < 0.001); mean decreases were 1.45-2.43 log10 copies/mL. Increased BIC exposures correlated with increased reduction in plasma HIV-1 RNA from baseline on day 11. Three participants on BIC (50 or 100 mg) achieved plasma HIV-1 RNA <50 copies/mL by end of study. Median Tmax ranged from 1.0 to 1.8 hours (day 1, postdose) and 1.3-2.7 hours (day 10), with median t1/2 ranging from 15.9 to 20.9 hours. No participant developed primary INSTI-R substitution through day 17. BIC was well tolerated, with no discontinuations because of adverse events.
CONCLUSIONS: BIC is a novel, potent, unboosted INSTI that demonstrated rapid, dose-dependent declines in HIV-1 RNA after 10 days of monotherapy. BIC was well tolerated, and displayed rapid absorption and a half-life supportive of once-daily therapy in HIV-infected subjects.

PMID: 28196003 [PubMed - indexed for MEDLINE]

Adverse Reactions to Contrast Material: A Canadian Update.

Can Assoc Radiol J. 2017 May;68(2):187-193

Authors: Morzycki A, Bhatia A, Murphy KJ

Abstract
Imaging techniques frequently employ contrast agents to improve image resolution and enhance pathology detection. These gadolinium- and iodine-based media, although generally considered safe, are associated with a number of adverse effects ranging from mild to severe. Reactions are classified as either anaphylactoid ("anaphylaxis-like") or nonanaphylactoid, depending on a number of elements that will be reviewed. Herein, we have summarized predisposing risk factors for adverse events resulting from the use of contrast, their associated pathophysiological mechanisms as well as known prophylaxis for the antitreatment of high-risk patients. In the unlikely event that a serious adverse reaction does occur, we have provided a comprehensive summary of treatment protocols. Our goal was to thoroughly evaluate the current literature regarding adverse reactions to radiocontrast agents and provide an up to date review for the health care provider.

PMID: 27745988 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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