High diagnosis rate for nonimmune hydrops fetalis with prenatal clinical exome from the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) Study

PurposeNonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and can be caused by both genetic and non-genetic etiologies. We explored incremental diagnostic yield of testing with prenatal exome sequencing (ES) for NIHF following a negative standard NIHF workup.MethodsParticipants enrolled into the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study met a strict definition of NIHF and had negative standard-of-care workup. Clinical trio ES from fetal samples and parental blood was performed at a CLIA-certified reference laboratory with clinical reports returned by geneticists and genetic counselors. Negative exomes were reanalyzed with information from subsequent ultrasounds and records.ResultsTwenty-two fetal exomes reported 11 (50%) diagnostic results and five possible diagnoses (22.7%). Diagnosed cases comprised seven de novodominant disorders, three recessive disorders, and one inherited dominant disorder including four Noonan syndromes (PTPN11, RAF1, RIT1, and RRAS2), three musculoskeletal disorders (RYR1, AMER1, and BICD2), two metabolic disorders (sialidosis and multiple sulfatase deficiency), one Kabuki syndrome, and one congenital anemia (KLF1).ConclusionThe etiology of NIHF predicts postnatal prognosis and recurrence risk in future pregnancies. ES provides high incremental diagnostic yield for NIHF after standard-of-care testing and should be considered in the workup.     

Private payer coverage policies for exome sequencing (ES) in pediatric patients: trends over time and analysis of evidence cited

PurposeExome sequencing (ES) is being adopted for neurodevelopmental disorders in pediatric patients. However, little is known about current coverage policies or the evidence cited supporting these policies. Our study is the first in-depth review of private payer ES coverage policies for pediatric patients with neurodevelopmental disorders.MethodsWe reviewed private payer coverage policies and examined evidence cited in the policies of the 15 largest payers in 2017, and trends in coverage policies and evidence cited (2015–2017) for the five largest payers.ResultsThere were four relevant policies (N = 5 payers) in 2015 and 13 policies (N = 15 payers) in 2017. In 2015, no payer covered ES, but by 2017, three payers from the original registry payers did. In 2017, 8 of the 15 payers covered ES. We found variations in the number and types of evidence cited. Positive coverage policies tended to include a larger number and range of citations.ConclusionWe conclude that more systematic assessment of evidence cited in coverage policies can provide a greater understanding of coverage policies and how evidence is used. Such assessments could facilitate the ability of researchers to provide the needed evidence, and the ability of clinicians to provide the most appropriate testing for patients.     

Psychological outcomes related to exome and genome sequencing result disclosure: a meta-analysis of seven Clinical Sequencing Exploratory Research (CSER) Consortium studies

PurposeAs exome and genome sequencing (ES/GS) enters the clinic, there is an urgent need to understand the psychological effects of test result disclosure. Through a Clinical Sequencing Exploratory Research (CSER), phase 1 (CSER1) Consortium collaboration, we evaluated participants’ psychological outcomes across multiple clinical settings.MethodsWe conducted a random effects meta-analysis of state anxiety (Hospital Anxiety and Depression Scale [HADS]/Generalized Anxiety Disorder 7-item), depressive symptoms (HADS/Personal Health Questionnaire 9-item), and multidimensional impact (i.e., test-related distress, uncertainty and positive impact: modified Multidimensional Impact of Cancer Risk Assessment/Feelings About Genomic Testing Results scale).ResultsAnxiety and depression did not increase significantly following test result disclosure. Meta-analyses examining mean differences from pre- to postdisclosure revealed an overall trend for a decrease in participants’ anxiety. We observed low levels of test-related distress and perceptions of uncertainty in some populations (e.g., pediatric patients) and a wide range of positive responses.ConclusionOur findings across multiple clinical settings suggest no clinically significant psychological harms from the return of ES/GS results. Some populations may experience low levels of test-related distress or greater positive psychological effects. Future research should further investigate the reasons for test-related psychological response variation.     

Pediatric adrenocortical tumors: morphological diagnostic criteria and immunohistochemical expression of matrix metalloproteinase type 2 and human leucocyte-associated antigen (HLA) class II antigens. Results from the Italian Pediatric Rare Tumor (TREP) Study project

Pediatric adrenocortical tumors are neoplasms that only rarely occur in pediatric patients. Their clinical behavior is often unpredictable, and the histologic criteria of malignancy used in adults are not always useful in children. The aim of this study was to validate the prognostic value of the pathologic criteria of Wieneke et al and to evaluate the potential prognostic expression of matrix metalloproteinase 2 and human leucocyte-associated antigen (HLA) class II antigens in a series of 20 pediatric patients affected by adrenocortical tumors, who were enrolled in the Italian Pediatric Rare Tumor (TREP) Study between 2000 and 2007. The age range was 0 to 17.5 years (mean, 7.28 years) with a male-female ratio of 1:2. The mean follow-up was 64.4 months. The histologic diagnoses were reviewed, and the cases were classified using the criteria for malignancy proposed by Wieneke et al. The immunohistochemical expression of matrix metalloproteinase 2 and HLA class II antigens was scored by semiquantitative analysis and compared with the clinicopathologic parameters and outcome. Based on the scoring system of Wieneke et al, 7 tumors were classified as malignant; 12 tumors, as benign; and only 1 tumor, with "unpredictable behavior." In all cases, the clinical behavior was consistent with the pathologic criteria of Wieneke et al. Notably, areas of regressive myxoid changes, not included among the criteria of Wieneke et al, were observed in all but 1 case of malignant tumors and only in 2 cases of benign tumors. Matrix metalloproteinase 2 was focally to diffusely expressed in all malignant and in most benign tumors. HLA class II antigens immunoreactivity was absent in all benign tumors and restricted to rare isolated cells in most malignant tumors. Our findings confirm that the pathologic scoring system of Wieneke et al is a simple and reproducible diagnostic tool to predict prognosis in pediatric adrenocortical tumors. Unlike in their adult counterpart, the expression of matrix metalloproteinase 2 or the loss of HLA class II antigens does not discriminate between benign and malignant tumors in children. Although pediatric adrenocortical tumors seem to be similar histologically to their adult counterparts, it is likely that they have distinctive molecular features.     

Cloning and sequencing of the 3-phosphoglycerate kinase (PGK) gene from Penicillium citrinum and its application to heterologous gene expression

The gene coding for 3-phosphoglycerate kinase (PGK) in ML-236B (compactin)-producing Penicillium citrinum was isolated from the recombinant phage lambda library using the corresponding Aspergillus nidulans pgk gene as a probe. The P. citrinum pgk gene has an open reading frame of 1,254 bp, encoding a protein of 417 amino acids with a predicted molecular weight of 44,079 daltons. The position of the two introns, 59 and 60 bp respectively, was deduced from an homology comparison with the sequence of the A. nidulans pgk gene. The PGK protein of P. citrinum shows extensive high homology to the PGKs of four other fungi: P. chrysogenum (93%), A. nidulans (84%), Trichoderma reesei (78%) and Saccharomyces cerevisiae (68%). Almost total conservation is found in P. citrinum of residues thought to be important for the structure and function of the yeast enzyme. The strong codon preference found has greater similarity to that in other filamentous fungi than in yeast. A DNA fragment encompassing the pgk gene was shown to hybridize a 1.35-kb poly(A)⁺RNA, sufficient to encode the PGK polypeptide. A fused gene, pgk-hpt, containing the putative pgk promoter and the open reading frame of the Escherichia coli hygromycin B phospho-transferase (hpt) gene was constructed, and was successfully used to transform P. citrinum to a hygromycin B (HmB)-resistant phenotype.     

Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease

The locus PKHD1 (polycystic kidney and hepatic disease 1) has been linked to all typical forms of the autosomal recessive polycystic kidney disease (ARPKD) and maps to chromosome 6p21.1-p12. We previously defined its genetic interval by the flanking markers D6S1714 and D6S1024. In our current work, we have fine-mapped the gene for the human P1 protein (MCM3), thought to be involved in the DNA replication process, to this critical region. We have also established its genomic structure. Mutation analyses using SSCP were performed in ARPKD patients' cDNA samples, leading to the exclusion of this gene as a candidate for this disorder. We also identified two intragenic polymorphisms that allowed families with critical recombination events to be evaluated. Although neither marker was informative in these individuals, they are the closest yet described for PKHD1 and may help to refine the candidate region.     

Cloning and characterization of a bifunctional glycosyl hydrolase from an antagonistic Pseudomonas putida strain P3(4)

A fluorescent pseudomonad strain P3(4) showing chitinolysis on chitinase detection agar and antagonism against Fusarium oxysporum f.sp dianthi causing vascular wilt of carnation was isolated from pea rhizosphere soil. PCR primers specific for glycosyl hydrolase family 5 (GH5) of Pseudomonas putida isolate KT2440 amplified a 947 bp fragment of the GH5 gene from P3(4). Cloning of this gene into Escherichia coli M15 using an expression vector pQE-30UA and screening on chitin and chitosan detection agar identified one positive clone (Pchi(+) ). Sequence analysis of the cloned insert revealed an open reading frame of 947 nucleotides corresponding to a protein of 315 amino acids with a predicted molecular mass of 38.0 kDa. The deduced amino acid sequence of the open reading frame (gene product/GH) showed 83-84% homology to the GH5 of P. putida strains F1 and KT2440, respectively. The purified enzyme was homogenous, as examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was visualized as single fluorescent band in native gel assay with 4-methylumbelliferyl-N -acetyl-β;-D-glucosaminide and glycol chitosan, respectively. For hydrolysis of 4-nitrophenyl-N -acetyl-β;-D-glucosaminide (pNP-(GlcNAc) and colloidal chitosan, the enzyme had an optimal temperature of 40 °C, and was stable within the temperature range of 10 °C to 40 °C. The enzyme showed an optimal pH of 3.5, with maximum stabilities at 5.0 and 5.5 for hydrolysis of pNP-(GlcNAc) and colloidal chitosan, respectively. Fe(3+) and Cu(2+) stimulated chitinase and chitosanase activities by 74.2 and 51.4%, respectively. The purified GH displayed 70 and 45% inhibition of spore germination of the pathogenic fungi, Fusarium oxysporum f.sp. dianthi and Alternaria solani, respectively.     

Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases.

The Cord Blood Transplantation Study (COBLT), sponsored by the National Heart, Lung, and Blood Institute, is a phase II multicenter study designed to evaluate the use of cord blood in allogeneic transplantation. In this report, we evaluated the outcomes of cord blood transplantation in 69 patients with lysosomal and peroxisomal storage diseases. Patients with mucopolysaccharidoses I to III, mucolipidoses (ML) II (n = 36), adrenoleukodystrophy (n = 8), metachromatic leukodystrophy (n = 6), Krabbe disease (n = 16), and Tay-Sachs disease (n = 3) were enrolled between August 1999 and June 2004. All patients received the same preparative regimen, graft-versus-host disease (GVHD) prophylaxis, and supportive care. End points included survival, engraftment, GVHD, and toxicity. Sixty-nine patients (64% men; 81% white) with a median age of 1.8 years underwent transplantation with a median cell dose of 8.7 x 10(7)/kg. One-year survival was 72% (95% confidence interval, 61%-83%). The cumulative incidence of neutrophil engraftment by day 42 was 78% (95% confidence interval, 67%-87%) at a median of 25 days. Grade II to IV acute GVHD occurred in 36% of patients. Cord blood donors are readily available for rapid transplantation. Cord blood transplantation should be considered as frontline therapy for young patients with lysosomal and peroxisomal storage diseases.     

Potency of Anidulafungin Compared to Nine Other Antifungal Agents Tested against Candida spp., Cryptococcus spp., and Aspergillus spp.: Results from the Global SENTRY Antimicrobial Surveillance Program (2008)

The SENTRY Antimicrobial Surveillance Program regularly monitors global susceptibility rates for a spectrum of both novel and established antifungal agents. Anidulafungin and the other echinocandins displayed sustained, excellent activity against Candida spp. and Aspergillus fumigatus, with ≥98% of MIC results at ≤2 μg/ml. Six yeast isolates (all Candida glabrata) showing caspofungin MIC values of ≥0.5 μg/ml were further analyzed for potential fks hot spot (HS) mutations; three isolates had confirmed mutations in the fks1 HS1 region (S645P), and three exhibited mutations in the fks2 HS1 region (S645F and S645P).Opportunistic fungal infections are increasing in incidence (18) and are associated with high rates of morbidity and mortality (1, 11, 13). The rise in prevalence of individuals with short-term neutropenia (cancer patients undergoing chemotherapy regimens), long-term immunosuppression (organ transplant patients), immune system disorders (patients with HIV/AIDS), or central venous catheters has coincided with the increased occurrence of problematic opportunistic fungal infections (11). At this time, only a limited number of azole and echinocandin antifungal agents are available for therapeutic intervention against these infections.Anidulafungin (9, 14-17) is a novel semisynthetic agent that targets cell wall structural integrity via noncompetitive inhibition of β-1,3-d-glucan synthesis, resulting in cell rupture and death. Excellent broad-spectrum in vitro and in vivo activities against a variety of fungal pathogens have been demonstrated (16). We present here contemporary data (2008) from the global SENTRY Antimicrobial Surveillance Program comparing the activity of anidulafungin to those of nine additional antifungal agents by use of reference methods (5-7).A collection of 1,201 clinical yeasts from bloodstream infections (BSI) and 79 molds from pneumonias (lower respiratory tract infections [LRTI]) in the United States, Europe, Latin America, and the Asia-Pacific region (APAC) was processed by Clinical and Laboratory Standards Institute (CLSI) methods and included (in rank order) Candida albicans (587 isolates), C. glabrata (218), C. parapsilosis (196), C. tropicalis (126), C. krusei (24), C. lusitaniae (19), C. dubliniensis (12), C. guilliermondii (4), C. kefyr (4), C. famata (3), C. rugosa (2), C. haemulonii (1), C. inconspicua (1), C. lambica (1), C. norvegensis (1), C. pelliculosa (1), and C. sake (1). The collection also included Cryptococcus neoformans (43 isolates), Aspergillus fumigatus (60), and 19 other molds (data not shown: Aspergillus flavus [3], Aspergillus niger [3], Fusarium spp. [4], Penicillium spp. [3], Rhizopus spp. [2], Bipolaris sp. [1], and Mucor sp. [1], as well as 2 molds not identified to the species level). Laboratories were instructed to submit unique BSI and LRTI isolates obtained in consecutive order, allowing prevalence of the fungal isolates in participating centers to be determined.All fungal isolates were identified at the participant''s medical center by established laboratory methods in use at each institution and confirmed at the central reference laboratory (JMI Laboratories, North Liberty, IA) using Vitek (bioMerieux, Hazelwood, MO) and conventional reference procedures (12, 19). All yeasts were tested by broth microdilution using the CLSI M27-A3 (5) standardized reference method. Preparation of inocula for molds followed procedures described in the CLSI M38-A2 reference method for filamentous fungi (7). Quality control (QC) isolates C. krusei ATCC 6258 and C. parapsilosis ATCC 22019 were used, and all QC results were within published ranges (6).Anidulafungin and voriconazole (Pfizer, Inc., New York, NY), amphotericin B, fluconazole, itraconazole, ketoconazole, and flucytosine (Sigma Chemical Co., St. Louis, MO), caspofungin (Merck Research Laboratories, Rahway, NJ), micafungin (Astellas Toyama Co., Ltd., Toyama, Japan), and posaconazole (Schering-Plough Research Institute, Kenilworth, NJ) were obtained as standard powders and prepared according to CLSI guidelines (5-7). The final concentration ranges (in μg/ml) were as follows: for anidulafungin, 0.001 to 32; for caspofungin and micafungin, 0.008 to 16; for amphotericin B, 0.12 to 8; for flucytosine and fluconazole, 0.5 to 64; for itraconazole, 0.015 to 2; and for posaconazole, voriconazole, and ketoconazole, 0.06 to 8. Antifungal dilution testing ranges were selected for maximal capture of MIC₅₀ and MIC₉₀ wild-type and mutant populations, including expanded ranges for newer and investigational agents to detect organism populations exhibiting potential resistance to these compounds. MIC values (yeasts and molds) and 90% minimal effective concentrations (MEC₉₀) (echinocandins, molds only) were determined as described in the CLSI reference methods (5, 7).Table ​Table11 displays the in vitro activities of 10 antifungal agents tested against yeast BSI isolates collected from the 2008 SENTRY Program. Anidulafungin was the most active agent against (MIC₉₀ in μg/ml) C. albicans (0.06), C. glabrata (0.12), C. tropicalis (0.06), and C. krusei (0.12) and was less potent against C. parapsilosis (MIC₉₀, 2 μg/ml) and C. guilliermondii (data not shown). The echinocandin potency against A. fumigatus was greatest for anidulafungin (MEC₉₀, 0.002 μg/ml) and caspofungin (MEC₉₀, 0.008 μg/ml) (Table ​(Table1).1). The results demonstrate the expanded utility of these agents against the most common mold species identified in lower respiratory tract infections.

TABLE 1.

In vitro activities of anidulafungin and nine other selected antifungal agents tested against yeast BSI isolates and mold LRTI isolates from the 2008 SENTRY Antimicrobial Surveillance Program (North America, Latin America, Europe, and Asia-Pacific region)

Role of tau kinases (CDK5R1 and GSK3B) in Parkinson's disease: a study from India

Glycogen synthase kinase-3β (GSK3B) and cyclin-dependent kinase 5 (CDK5) are the 2 major protein kinases involved in abnormal phosphorylation of tau. To determine their potential role in the pathogenesis of Parkinson's disease (PD) we analyzed 2 functional single nucleotide polymorphisms (SNPs) of GSK3B (rs334558 and rs6438552) and rs735555 of CDK5 regulatory subunit 1 (CDK5R1) in 373 PD cases and 346 healthy controls of eastern India. The C,C and T,C haplotypes of GSK3B were respectively moderately associated with increased risk and protection for late onset PD (LOPD) (odds ratio [OR], 1.399; 95% confidence interval [CI], 1.069-1.829; p = 0.015, and OR, 0.436; 95% CI, 0.222-0.853; p = 0.016, respectively). Moreover, moderate to significant interaction between different loci were observed for the entire PD cohort or late onset PD only. However, among these interactions, individuals carrying the (C/C) genotype at both loci (rs6438552 and rs735555) had almost twice the risk of developing PD than those without this genotypic combination (OR, 1.871; 95% CI, 1.181-2.964; p = 0.009). Thus, synergistic effect between the 2 major tau kinases, through these SNPs, appears to determine the risk profile for PD.     

Clinicobacteriological study of Pasteurella multocida infection as a zoonosis. (2)--Comparisons of P. multocida separated from patients and their pet dogs and cats]

A total of 17 strains of Pasteurella multocida, of which 13 were isolated from patients treated at Nihon University Itabashi Hospital or Nihon University Surugadai Hospital between April, 1984 and March, 1991 and 4 from 1 dog and 3 cats kept by the patients, were evaluated with respect to their biochemical properties, sensitivity to drugs, and serotype. The isolated strains were all considered to be Pasteurella multocida subsp. multocida because of the agreement of their responses to indole, sorbitol and dulcitol with those of this subspecies, except for 1 sorbitol-negative strain of Pasteurella multocida subsp. septica isolated from 1 patient who had been bitten by a cat. All the isolated strains showed high sensitivities to various drugs. The serotype was capsular type A, which is often observed in cats and dogs, in 7 strains, which consisted of 6 of the 7 strains derived from the airway of the patients and 1 of the 6 strains derived from bit or scratch wound. The remaining strains could not be classified. Five morphological types, namely 1, 3, 3.8, 6, and 8 were observed. In 2 patients, Pasteurella multocida subsp. multocida of the same serotype was also isolated from their cats. One of these patients had intimate contact with the cat including kissing. Our findings suggest that: 1) Pasteurella multocida subsp. multocida has been responsible for most conventional cases of Pasteurella multocida infection. 2) Strains isolated from patients differ in the capsular type according to the disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

C3b receptor (CR1) on phagocytic cells from SLE patients: analysis of the defect and familial study.

In vitro CR1-dependent phagocytosis of C3b-coated erythrocytes, by monocytes and PMN, was found to be significantly decreased in SLE patients. This was in many cases related to a specific defect of CR1 receptors, since the FcR-ingestion of EIgG was normal. On the other hand, CR1 levels of PMN stimulated by FMLP were also found to be decreased in SLE patients, while both the expression of circulating PMN (cells isolated at 4 degrees C) and the total cellular CR1 content were normal. On the basis of the available data, we propose that the impaired phagocytosis is due to a functional defect of CR1 or a defective anchorage of the receptor to the plasma membrane, possibly related to the decreased capacity of CR1 to be up-regulated by FMLP. To study the importance of the genetic background in the CR1 abnormalities, the families of 22 young SLE patients, in which the onset of the disease had occurred before the age of 15, were studied. The expression of CR1 on erythrocytes, and the total CR1 content of PMN, in parents and siblings of these patients did not differ significantly from normal controls. By contrast, the ingestion of EIgGC3b by PMN from healthy relatives of these patients was decreased (65% of the normal mean of PI), while EIgG phagocytosis was normal. A relation between this CR1 functional defect and the familial occurrence of autoimmune disorders is therefore possible.     

低氧微环境对P(3HB-co-4HB)与小鼠骨髓间充质干细胞共培养形成心肌补片影响的实验研究

目的探究低氧微环境对小鼠骨髓间充质干细胞(mouse bone marrow mesenchymal stem cells,mMSCs)与聚3羟基丁酸酯-co-4羟基丁酸酯[3-hydroxybutyrate-co-4-hydroxybutyrate,P(3HB-co-4HB)]材料共培养形成心肌补片的影响,为细胞移植术治疗心肌梗死提供一种更有效的心肌补片。方法全骨髓培养法提取小鼠骨髓间充质干细胞(mMSCs),取5代mMSCs流式细胞术鉴定表面抗原。将P(3HB-co-4HB)与小鼠骨髓间充质干细胞共培养制作成细胞补片,随机分为常氧组和低氧组,每组各10个样本,0、12、24 h分别用CCK-8法测定细胞增殖情况;扫描电子显微镜(scanning electron microscope,SEM)观察补片存活、黏附、生长情况。加入诱导剂5-氮杂胞苷2周后,免疫荧光检测两组心肌肌钙蛋白T(cTnT)的表达情况。结果在共培养24 h后,CCK-8法测定低氧组OD值(0.349±0.038)显著大于常氧组(0.308±0.025)( n =10, P <0.05),扫描电子显微镜观察到低氧组P(3HB-co-4HB)材料上细胞数量更多,细胞与材料之间的黏附牢固,细胞形态正常。免疫荧光显示低氧组cTnT表达比常氧组更加显著。结论相对于常氧条件,低氧微环境可促进骨髓间充质干细胞在P(3HB-co-4HB)材料上的黏附、存活、增殖、分化,形成一种更有效的心肌补片。     

Characterization of nontypeable rotavirus strains from the United States: identification of a new rotavirus reassortant (P2A[6],G12) and rare P3[9] strains related to bovine rotaviruses

Among 1316 rotavirus specimens collected during strain surveillance in the United States from 1996 to 1999, most strains (95%) belonged to the common types (G1 to G4 and G9), while 5% were mixed infections of common serotypes, rare strains, or not completely typeable. In this report, 2 rare (P[9],G3) and 2 partially typeable (P[6],G?; P[9],G?) strains from that study were further characterized. The P[6] strain was virtually indistinguishable by hybridization analysis in 10 of its 11 gene segments with recently isolated P2A[6],G9 strains (e.g., U.S.1205) from the United States, but had a distinct VP7 gene homologous (94.7% a.a. and 90.2% nt) to the cognate gene from P1B[4],G12 reference strain L26. Thus, this serotype P2A[6],G12 strain represents a previously unrecognized reassortant. Three P3[9] strains were homologous (97.8-98.2% aa) in the VP8 region of VP4 to the P3[9],G3 feline-like reference strain AU-1, but had a high level of genome homology to Italian bovine-like, P3[9],G3 and P3[9],G6 rotavirus strains. Two of the U.S. P3[9] strains were confirmed to be type G3 (97.2-98.2% VP7 aa homology with reference G3 strain AU-1), while the other was most similar to Italian bovine-like strain PA151 (P3[9],G6), sharing 99.0% a.a. homology in VP7. Cross-neutralization studies confirmed all serotype assignments and represented the first detection of these rotavirus serotypes in the United States. The NSP4 genes of all U.S. P3[9] strains and rotavirus PA151 were most closely related to the bovine and equine branch within the DS-1 lineage, consistent with an animal origin. These results demonstrate that rare strains with P and G serotypes distinct from those of experimental rotavirus vaccines circulate in the United States, making it important to understand whether current vaccine candidates protect against these strains.     

Efficacy and safety of self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (MND-2119) versus highly purified eicosapentaenoic acid ethyl ester in patients with hypertriglyceridemia: Results from a 12-week randomized,double-blind,active-controlled,phase 3 study

BackgroundIn Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E, which can be administered once-daily.ObjectiveThe objective of this study was to assess non-inferiority in the efficacy of MND-2119 in patients with hypertriglyceridemia compared with highly purified EPA-E.MethodsIn this multicenter, 12-week, double-blind study, patients with high triglyceride (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=145), MND-2119 4 g/day (n=145), EPA-E 1.8 g/day (n=145) or EPA-E 2.7 g/day (n=145). The primary endpoint was percentage change in TG levels from baseline to end of treatment.ResultsMND-2119 2, 4 g/day and EPA-E 1.8, 2.7 g/day reduced TG levels from baseline by ?10.09%, ?15.51%, ?9.30%, and ?8.80%, respectively. The TG reduction rate of MND-2119 2 g/day was non-inferior to that of EPA-E 1.8 g/day (LS mean difference: -0.42, 95%CI: -5.76 to 4.91). Moreover, the TG reduction rate of MND-2119 4 g/day was superior to that of MND-2119 2 g/day (LS mean difference: -5.74, 95%CI: -10.59 to -0.89). There were no remarkable safety differences between MND-2119 2 g/day and EPA-E 1.8 g/day and between MND-2119 4 g/day and EPA-E 2.7 g/day.ConclusionNon-inferiority of MND-2119 2 g/day to EPA-E 1.8 g/day for efficacy, and superiority of MND-2119 4 g/day over MND-2119 2 g/day for efficacy were verified. MND-2119 was safe and well tolerated.