Continuous glucose monitoring abnormalities in cystic fibrosis youth correlate with pulmonary function decline.

J Cyst Fibros. 2018 Mar 23;:

Authors: Chan CL, Vigers T, Pyle L, Zeitler PS, Sagel SD, Nadeau KJ

Abstract
BACKGROUND: To characterize glucose patterns with continuous glucose monitoring (CGM) in cystic fibrosis (CF) and assess relationships between CGM and clinical outcomes.
METHODS: 110 CF youth and healthy controls (HC), 10-18 years, wore CGM up to 7 days. Correlations between CGM and lung function and BMI z-score change over the prior year were determined.
RESULTS: Multiple CGM measures were higher in CF Normal Glycemic (CFNG) youth versus HC (peak glucose, excursions >140 mg/dl/day, %time > 140 mg/dl, standard deviation (SD) and mean amplitude of glycemic excursions (MAGE)). Hypoglycemia was no different among groups. In CF, decline in FEV1% and FVC% correlated with maximum CGM glucose, excursions >200 mg/dl/day, SD, and MAGE.
CONCLUSIONS: CFNG youth have higher glucoses and glucose variability than HC on CGM. Higher and more variable glucoses correlate with lung function decline. Whether earlier treatment of CGM abnormalities improves lung function in CF requires further study.

PMID: 29580828 [PubMed - as supplied by publisher]

A multi-host approach to identify a transposon mutant of Pseudomonas aeruginosa LESB58 lacking full virulence.

BMC Res Notes. 2018 Mar 27;11(1):198

Authors: Gagné-Thivierge C, Kukavica-Ibrulj I, Filion G, Dekimpe V, Tan SGE, Vincent AT, Déziel É, Levesque RC, Charette SJ

Abstract
OBJECTIVE: Pseudomonas aeruginosa is an opportunistic bacterial pathogen well known to cause chronic lung infections in individuals with cystic fibrosis (CF). Some strains adapted to this particular niche show distinct phenotypes, such as biofilm hyperproduction. It is necessary to study CF clinical P. aeruginosa isolates, such as Liverpool Epidemic Strains (LES), to acquire a better understanding of the key genes essential for in vivo maintenance and the major virulence mechanisms involved in CF lung infections. Previously, a library of 9216 mutants of the LESB58 strain were generated by signature-tagged mutagenesis (STM) and screened in the rat model of chronic lung infection, allowing the identification of 163 STM mutants showing defects in in vivo maintenance.
RESULTS: In the present study, these 163 mutants were successively screened in two additional surrogate host models (the amoeba and the fruit fly). The STM PALES_11731 mutant was the unique non-virulent in the three hosts. A competitive index study in rat lungs confirmed that the mutant was 20-fold less virulent than the wild-type strain. This study demonstrated the pertinence to use a multi-host approach to study the genetic determinants of P. aeruginosa strains infecting CF patients.

PMID: 29580289 [PubMed - in process]

Current and future molecular approaches in the diagnosis of cystic fibrosis.

Expert Rev Respir Med. 2018 Mar 27;:

Authors: Bergougnoux A, Taulan-Cadars M, Claustres M, Raynal C

Abstract
INTRODUCTION: Cystic Fibrosis is among the first diseases to have general population genetic screening tests and one of the most common indications of prenatal and preimplantation genetic diagnosis for single gene disorders. During the past twenty years, thanks to the evolution of diagnostic techniques, our knowledge of CFTR genetics and pathophysiological mechanisms involved in cystic fibrosis has significantly improved. Areas covered: Sanger sequencing and quantitative methods greatly contributed to the identification of more than 2,000 sequence variations reported worldwide in the CFTR gene. We are now entering a new technological age with the generalization of high throughput approaches such as Next Generation Sequencing and Droplet Digital PCR technologies in diagnostics laboratories. These powerful technologies open up new perspectives for scanning the entire CFTR locus, exploring modifier factors that possibly influence the clinical evolution of patients, and for preimplantation and prenatal diagnosis. Expert commentary: Such breakthroughs would, however, require powerful bioinformatics tools and relevant functional tests of variants for analysis and interpretation of the resulting data. Ultimately, an optimal use of all those resources may improve patient care and therapeutic decision-making.

PMID: 29580110 [PubMed - as supplied by publisher]

The Standoff.

J Am Coll Radiol. 2017 04;14(4):547-548

Authors: Brown SD

PMID: 28274692 [PubMed - indexed for MEDLINE]

Whole-Genome Linkage Analysis with Whole-Exome Sequencing Identifies a Novel Frameshift Variant in NEFH in a Chinese Family with Charcot-Marie-Tooth 2: A Novel Variant in NEFH for Charcot-Marie-Tooth 2.

Neurodegener Dis. 2018 Mar 27;18(2-3):74-83

Authors: Bian X, Lin P, Li J, Long F, Duan R, Yuan Q, Li Y, Gao F, Gao S, Wei S, Li X, Sun W, Gong Y, Yan C, Liu Q

Abstract
BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common neurodegenerative disorder of the peripheral nervous system. More than 50 genes/loci were found associated with the disease. We found a family with autosomal-dominant CMT2.
OBJECTIVE: To reveal the pathogenic gene of the family and further investigate the function of the variant.
METHODS: DNA underwent whole-genome linkage analysis for all family members and whole-exome sequencing for 2 affected members. Neurofilament light polypeptide and wild-type or mutant neurofilament heavy polypeptide (NEFH) were co-transfected into SW13 (vim-) cells. The nefh-knockdown zebrafish model was produced by using morpholino antisense oligonucleotides.
RESULTS: We identified a novel insertion variant (c.3057insG) in NEFH in the family. The variant led to the loss of a stop codon and an extended 41 amino acids in the protein. Immunofluorescence results revealed that mutant NEFH disrupted the neurofilament network and induced aggregation of NEFH protein. Knockdown of nefh in zebrafish caused a slightly or severely curled tail. The motor ability of nefh-knockdown embryos was impaired or even absent, and the embryos showed developmental defects of axons in motor neurons. The abnormal phenotype and axonal developmental defects could be rescued by injection of human wild-type but not human mutant NEFH mRNA.
CONCLUSIONS: We identified a novel stop loss variant in NEFH that is likely pathogenic for CMT2, and the results provide further evidence for the role of an aberrant assembly of neurofilament in CMT.

PMID: 29587262 [PubMed - as supplied by publisher]

[EXOME ANALYSIS - A GAME CHANGER IN PEDIATRICS].

Harefuah. 2018 Mar;157(3):188-191

Authors: Ta-Shma A, Edvardson S, Elpeleg O, Stepensky P

Abstract
INTRODUCTION: Thirteen years after the completion of the human genome project, the determination of the genomic sequence of the coding parts of the DNA (the exones, hence the exome), has turned into a primary diagnostic tool in daily use in clinical practice. The Department of Genetics at Hadassah was the first in Israel to introduce exome analysis as a robust diagnostic tool into the pediatric departments. Till now 2600 exomes were analyzed at Hadassah, 850 of them in 2016 alone. Exome analysis is cheap and fast, enabling precise and non-invasive diagnosis for a vast array of genetic disorders and congenital malformations. The unique composition of the population which the hospital serves (marked by a high rate of consanguinity) enabled reaching diagnosis in 65% of the cases, twice the rate in medical centers worldwide. The results of this analysis enable genetic counseling to patients' families and prevention of serious disorders. Moreover, the results contribute to the understanding of the biological basis of newly identified disorders and in certain cases assist in the management of the patients. The major limitation of exome analysis is the multitude of identified variants which exist in any individual and which challenge our ability to pick the disease-causing variant. In the case of a disease-causing variant in a new gene, experimental proof is required to validate the causality of the variant; occasionally, an incidental finding with possible clinical significance is identified, raising serious ethical concerns. In this article, we will review the use of this technology through the experience of three pediatric departments at Hadassah.

PMID: 29582952 [PubMed - in process]

Whole exome sequencing reveals a novel missense mutation in the MARS gene related to a rare Charcot-Marie-Tooth neuropathy type 2U.

J Peripher Nerv Syst. 2018 Mar 26;:

Authors: Sagi-Dain L, Shemer L, Zelnik N, Zoabi Y, Sadeh O, Adir V, Schif A, Peleg A

Abstract
BACKGROUND: Charcot-Marie-Tooth (CMT) is a heterogeneous group of progressive disorders, characterized by chronic motor and sensory polyneuropathy. This hereditary disorder is related to numerous genes and varying inheritance patterns. Thus, many patients do not reach a final genetic diagnosis.
PATIENT: We describe a 13-years old girl presenting with progressive bilateral leg weakness and gait instability. Extensive laboratory studies and spinal Magnetic resonance imaging scan were normal. Nerve conduction studies revealed severe lower limb peripheral neuropathy with prominent demyelinative component. Following presumptive diagnosis of chronic inflammatory demyelinating polyneuropathy, the patient received treatment with steroids and intravenous immunoglobulins courses for several months, with no apparent improvement.
RESULTS: Whole exome sequencing revealed a novel heterozygous c.2209C>T (p.Arg737Trp) mutation in the MARS gene (OMIM 156560). This gene has recently been related to CMT type 2U. In-silico prediction programs classified this mutation as a probable cause for protein malfunction. Allele frequency data reported this variant in 0.003% of representative Caucasian population. Family segregation analysis study revealed that the patient had inherited the variant from her 60-years old mother, reported as healthy. Neurologic examination of the mother demonstrated decreased tendon reflexes, while nerve conduction studies were consistent with demyelinative and axonal sensory-motor polyneuropathy.
CONCLUSION: Our report highlights the importance of next generation sequencing approach to facilitate the proper molecular diagnosis of highly heterogeneous neurologic disorders. Amongst other numerous benefits, this approach might prevent unnecessary diagnostic testing and potentially harmful medical treatment. Charcot-Marie-Tooth disease (CMT); CMT2U; MARS.

PMID: 29582526 [PubMed - as supplied by publisher]

Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results.

Clin Res Cardiol. 2018 Mar 26;:

Authors: Chua HC, Servatius H, Asatryan B, Schaller A, Rieubland C, Noti F, Seiler J, Roten L, Baldinger SH, Tanner H, Fuhrer J, Haeberlin A, Lam A, Pless SA, Medeiros-Domingo A

Abstract
OBJECTIVE: Unexplained cardiac arrest (UCA) is often the first manifestation of an inherited arrhythmogenic disease. Genetic testing in UCA is challenging due to the complexities of variant interpretation in the absence of supporting cardiac phenotype. We aimed to investigate if a KCNQ1 variant [p.(Pro64_Pro70del)], previously reported as pathogenic, contributes to the long-QT syndrome phenotype, co-segregates with disease or affects KCNQ1 function in vitro.
METHODS: DNA was extracted from peripheral blood of a 22-year-old male after resuscitation from UCA. Targeted exome sequencing was performed using the TruSight-One Sequencing Panel (Illumina). Variants in 190 clinically relevant cardiac genes with minor allele frequency < 1% were analyzed according to the guidelines of the American College of Medical Genetics. Functional characterization was performed using site-directed mutagenesis, expression in Xenopus laevis oocytes using the two-electrode voltage-clamp technique.
RESULTS: The 12-lead ECG, transthoracic echocardiography and coronary angiography after resuscitation showed no specific abnormalities. Two variants were identified: c.190_210del in-frame deletion in KCNQ1 (p.Pro64_Pro70del), reported previously as pathogenic and c.2431C > A in PKP2 (p.Arg811Ser), classified as likely benign. Two asymptomatic family members with no evident phenotype hosted the KCNQ1 variant. Functional studies showed that the wild-type and mutant channels have no significant differences in current levels, conductance-voltage relationships, as well as activation and deactivation kinetics, in the absence and presence of the auxiliary subunit KCNE1.
CONCLUSIONS: Based on our data and previous reports, available evidence is insufficient to consider the variant KCNQ1:c.190_210del as pathogenic. Our findings call for cautious interpretation of genetic tests in UCA in the absence of a clinical phenotype.

PMID: 29582136 [PubMed - as supplied by publisher]

Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility.

Eur J Hum Genet. 2018 Mar 26;:

Authors: Yıldırım Y, Ouriachi T, Woehlbier U, Ouahioune W, Balkan M, Malik S, Tolun A

Abstract
In affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We detected six sibs afflicted with a unique combination of digit malformation that includes brachydactyly, symphalangism and zygodactyly plus infertility in males owing to azoospermia, sperm immotility or necrospermia, which we hypothesised to have arisen from a defect in a single gene. We mapped the disease locus and by exome sequencing identified in patients homozygous missense variants bone morphogenetic protein receptor type IB (BMPR1B) c.640C>T (p.(Arg214Cys)) and alpha-2 pyruvate dehydrogenase (PDHA2) c.679A>G (p.(Met227Val)). Structural protein modelling, protein sequence conservation and in silico analysis indicate that both variants affect protein function. BMPR1B is known to be responsible for autosomal dominant brachydactyly and autosomal recessive acromesomelic chondrodysplasia. Our findings show that also recessive complex digit malformation can be caused by BMPR1B variant and not all biallelic BMPR1B variants cause acromesomelic dysplasia. PDHA2 is a novel candidate gene for male infertility; the protein product is a mitochondrial enzyme with highest expression in ejaculated sperm. Our findings are a unique example of two linked variants, ~ 711 Kb apart, in different genes that together manifest as a novel syndrome. They demonstrate that exome sequencing and not candidate gene approach should be employed in disease gene hunt, defining new diseases and genetic testing, to rule out the coincidental presence of two variants contributing together to the phenotype, which may be discerned as a novel disease.

PMID: 29581481 [PubMed - as supplied by publisher]

Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea.

Sci Rep. 2018 Mar 26;8(1):5214

Authors: Tong W, Wang Y, Lu Y, Ye T, Song C, Xu Y, Li M, Ding J, Duan Y, Zhang L, Gu W, Zhao X, Yang XA, Jin D

Abstract
Neurodevelopmental delay accompanied unexplained dyspnea is a highly lethal disease in clinic. This study is to investigate the performance characteristics of trio whole exome sequencing (Trio-WES) in a pediatric setting by presenting our patient cohort and displaying the diagnostic yield. A total of 31 pediatric patients showing neurodevelopmental delay accompanied unexplained dyspnea were admitted to our hospital and referred for molecular genetic testing using Trio-WES. Eight genes namely MMACHC, G6PC, G6PT, ETFDH, OTC, NDUFAF5, SLC22A5, and MAGEL2 were suspected to be responsible for the onset of the clinical symptoms and 6 variants were novel. Standard interpretation according to ACMG guideline showed that the variants were pathogenic. Finally, diagnosis of methylmalonic aciduria and homocystinuria, glycogen storage disease, ornithine transcarbamylase deficiency, glutaric acidemia II, mitochondrial complex 1 deficiency, carnitine deficiency, and Schaaf-Yang syndrome was made in 12 out of the 31 patients. Trio-WES is an effective means for molecular diagnosis of infantile neurodevelopmental delay accompanied unexplained dyspnea. As for molecular etiology identification, when routine potential monogenetic inheritance patterns including de novo, autosomal recessive, autosomal dominant, and X-linked recessive inheritance analysis is negative, physicians should take into account imprinted genes.

PMID: 29581464 [PubMed - in process]

Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial.

J Clin Oncol. 2018 Mar 27;:JCO2017760793

Authors: Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman JM, Collins GP, Ramchandren R, Cohen JB, De Boer JP, Kuruvilla J, Savage KJ, Trneny M, Shipp MA, Kato K, Sumbul A, Farsaci B, Ansell SM

Abstract
Purpose Genetic alterations causing overexpression of programmed death-1 ligands are near universal in classic Hodgkin lymphoma (cHL). Nivolumab, a programmed death-1 checkpoint inhibitor, demonstrated efficacy in relapsed/refractory cHL after autologous hematopoietic cell transplantation (auto-HCT) in initial analyses of one of three cohorts from the CheckMate 205 study of nivolumab for cHL. Here, we assess safety and efficacy after extended follow-up of all three cohorts. Methods This multicenter, single-arm, phase II study enrolled patients with relapsed/refractory cHL after auto-HCT treatment failure into cohorts by treatment history: brentuximab vedotin (BV)-naïve (cohort A), BV received after auto-HCT (cohort B), and BV received before and/or after auto-HCT (cohort C). All patients received nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary end point was objective response rate per independent radiology review committee. Results Overall, 243 patients were treated; 63 in cohort A, 80 in cohort B, and 100 in cohort C. After a median follow-up of 18 months, 40% continued to receive treatment. The objective response rate was 69% (95% CI, 63% to 75%) overall and 65% to 73% in each cohort. Overall, the median duration of response was 16.6 months (95% CI, 13.2 to 20.3 months), and median progression-free survival was 14.7 months (95% CI, 11.3 to 18.5 months). Of 70 patients treated past conventional disease progression, 61% of those evaluable had stable or further reduced target tumor burdens. The most common grade 3 to 4 drug-related adverse events were lipase increases (5%), neutropenia (3%), and ALT increases (3%). Twenty-nine deaths occurred; none were considered treatment related. Conclusion With extended follow-up, responses to nivolumab were frequent and durable. Nivolumab seems to be associated with a favorable safety profile and long-term benefits across a broad spectrum of patients with relapsed/refractory cHL.

PMID: 29584546 [PubMed - as supplied by publisher]

Upper Airway Stimulation for Obstructive Sleep Apnea: 5-Year Outcomes.

Otolaryngol Head Neck Surg. 2018 Mar 01;:194599818762383

Authors: Woodson BT, Strohl KP, Soose RJ, Gillespie MB, Maurer JT, de Vries N, Padhya TA, Badr MS, Lin HS, Vanderveken OM, Mickelson S, Strollo PJ

Abstract
Objective To present 5-year outcomes from a prospective cohort of patients with obstructive sleep apnea (OSA) who were treated with upper airway stimulation (UAS) via a unilateral hypoglossal nerve implant. Study Design A multicenter prospective cohort study. Setting Industry-supported multicenter academic and clinical trial. Methods From a cohort of 126 patients, 97 completed protocol, and 71 consented to a voluntary polysomnogram. Those having continuous positive airway pressure failure with moderate to severe OSA, body mass index <32 kg/m2, and no unfavorable collapse on drug-induced sleep endoscopy were enrolled in a phase 3 trial. Prospective outcomes included apnea-hypopnea index (AHI), oxygen desaturation index, and adverse events, as well as measures of sleepiness, quality of life, and snoring. Results Patients who did and did not complete the protocol differed in baseline AHI, oxygen desaturation index, and Functional Outcomes of Sleep Questionnaire scores but not in any other demographics or treatment response measures. Improvement in sleepiness (Epworth Sleepiness Scale) and quality of life was observed, with normalization of scores increasing from 33% to 78% and 15% to 67%, respectively. AHI response rate (AHI <20 events per hour and >50% reduction) was 75% (n = 71). When a last observation carried forward analysis was applied, the responder rate was 63% at 5 years. Serious device-related events all related to lead/device adjustments were reported in 6% of patients. Conclusions Improvements in sleepiness, quality of life, and respiratory outcomes are observed with 5 years of UAS. Serious adverse events are uncommon. UAS is a nonanatomic surgical treatment with long-term benefit for individuals with moderate to severe OSA who have failed nasal continuous positive airway pressure.

PMID: 29582703 [PubMed - as supplied by publisher]

Long-term tolerability, immunogenicity and efficacy of Nuwiq® (human-cl rhFVIII) in children with severe haemophilia A.

Haemophilia. 2018 Mar 26;:

Authors: Klukowska A, Szczepański T, Vdovin V, Knaub S, Bichler J, Jansen M, Dzhunova I, Liesner RJ

Abstract
INTRODUCTION: Nuwiq® (human-cl rhFVIII, simoctocog alfa) is a 4th generation recombinant human FVIII, without chemical modification or fusion with any other protein, produced in a human cell line.
AIM/METHODS: This study (GENA-13) was an extension of the GENA-03 study in which previously treated children aged 2-12 years with severe haemophilia A received Nuwiq® prophylaxis for ≥6 months. GENA-13 examined long-term tolerability, immunogenicity and efficacy of Nuwiq® prophylaxis in children.
RESULTS: Of 59 patients enrolled in GENA-03, 49 continued Nuwiq® prophylaxis in GENA-13 for a median (range) of 30.0 (9.5-52.0) months. No patient withdrew due to drug-related adverse events or developed inhibitors. Only 2 of 20 518 infusions were associated with possibly related adverse events (dyspnoea, fever). The estimated annualized bleeding rate (ABR) was 0.67 (95% CI: 0.44, 1.02) for spontaneous and 2.88 (95% CI: 1.86, 4.46) for all bleeds. Younger children (2-5 years) had lower ABRs than children aged 6-12 years. Annualized bleeding rates were reduced in GENA-13 vs GENA-03, especially for spontaneous bleeds in younger children (71% reduction; ABR ratio 0.29 [95% CI: 0.11, 0.74]). Nuwiq® efficacy was rated as excellent/good in the treatment of 83.0% of 305 evaluated breakthrough bleeds. Surgical prophylaxis with Nuwiq® was rated as excellent for all 17 assessed procedures.
CONCLUSION: Long-term treatment with Nuwiq® for the prevention of bleeds in children with severe haemophilia A was well tolerated, effective and reduced spontaneous bleeding by up to 70% compared with GENA-03.

PMID: 29582516 [PubMed - as supplied by publisher]

Concurrent Chemoradiotherapy with or without Anti-EGFR-Targeted Treatment for Stage II-IVb Nasopharyngeal Carcinoma: Retrospective Analysis with a Large Cohort and Long Follow-up.

Theranostics. 2017;7(8):2314-2324

Authors: You R, Hua YJ, Liu YP, Yang Q, Zhang YN, Li JB, Li CF, Zou X, Yu T, Cao JY, Zhang MX, Jiang R, Sun R, Mo HY, Guo L, Cao KJ, Lin AH, Sun Y, Qian CN, Ma J, Chen MY

Abstract
We examined the benefits of the combination of anti-EGFR targeted treatment, cetuximab (CTX) or nimotuzumab (NTZ) and concurrent platinum-based chemoradiotherapy (CCRT) compared with CCRT alone in patients with stage II - IVb nasopharyngeal carcinoma (NPC). A total of 1,628 eligible patients with stage II - IVb NPC, who received CCRT (three cycles of 100 mg/m2 cisplatin every 3 weeks with intensity-modulated radiotherapy) with or without CTX or NTZ between June 2009 and December 2013 were included in the analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 878 patients was created by matching each patient who received CTX or NTZ plus CCRT with no more than four patients who received CCRT alone (1:4). Efficacy and safety were compared between CTX/NTZ plus CCRT and CCRT alone arms. Compared with CCRT alone, treatment with CTX/NTZ plus CCRT was associated with a significantly increased overall survival (3-year OS, 96.6% vs. 92.9%, P = 0.015), improved disease-free survival (3-year DFS, 93.5% vs 86.9%, P = 0.028), and improved distant metastasis-free survival (3-year DMFS, 94.6% vs 89.3%, P = 0.030). Increased rate of CTX related-skin reaction and mucositis was observed in the CTX plus CCRT arm. Multivariate analysis demonstrated the combination of CTX/NTZ was a significant protective factor for OS, DFS, and DMFS in patients treated with CCRT. Our analysis suggests that the addition of CTX/NTZ to CCRT is more effective for maximizing survival in patients with stage II-IVb NPC compared with CCRT alone.

PMID: 28740554 [PubMed - indexed for MEDLINE]

Safety and Immunogenicity of a 9-Valent Human Papillomavirus Vaccine Administered to 9- to 15-Year-Old Japanese Girls.

Jpn J Infect Dis. 2017 Jul 24;70(4):368-373

Authors: Iwata S, Murata S, Rong Han S, Wakana A, Sawata M, Tanaka Y

Abstract
A 9-valent human papillomavirus (HPV 6/11/16/18/31/33/45/52/58) virus-like particle vaccine (9vHPV) has been proven highly efficacious in preventing anogenital diseases related to HPV, in a pivotal phase III study for women aged 16-26 years. Here, we report the results of an open-label phase III study conducted to bridge the gap between the findings in women aged 16-26 years and Japanese girls aged 9-15 years. All subjects (n = 100) received a 3-dose regimen of 9vHPV vaccine on day 1 and at months 2 and 6. Anti-HPV serological assays were performed on day 1 and at months 7, 12, 24, and 30. At month 7 (4 weeks after the third dose), 100% of the subjects exhibited seroconversion for each type of HPV. Increases in geometric mean of the titers for anti-HPV 6/11/16/18/31/33/45/52/58 in the subjects were similar to those in Japanese women aged 16-26 years in a previous phase III study. Persistence of the anti-HPV response was observed for 2 years after administration of the third dose. In addition, administration of the 9vHPV vaccine was generally well-tolerated in Japanese girls.

PMID: 28003597 [PubMed - indexed for MEDLINE]

[MODERN ASPECTS OF THE SAFE USE OF EXTENSION QT INTERVAL MEDICINES.]

Anesteziol Reanimatol. 2016 Sep;61(5):386-390

Authors: Shikh EV, Ismaailov AD, Dorofeeva MN, Sizava ZM

Abstract
Prolongation of QTinterval is apredictor offatal cardiac arrhythmias and sudden death. In clinical practice, medicines with possible and conditional risk of QTprolongation are combine. The danger of such interactions could be enhanced if medi- cines interact themselves at metabolic rate. The interaction of drugs with possible and conditional risk of QTprolongation and interaction of these drugs with drugs that can influence the metabolic activity of cytochrome P450 isoenzymes require specific attention from physicians. Predictability of QTprolongation by drug-drug interactions at metabolic rate in drug administration will increase the safety of pharmacotherapy of drugs with possible and conditional risk of QTprolongation.

PMID: 29489109 [PubMed - indexed for MEDLINE]

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