Effectiveness of a flow confirmation study of a central venous port of the upper arm versus the chest wall in patients with suspected system-related mechanical complications.

BACKGROUND: If mechanical complications associated with a central venous port (CVP) system are suspected, evaluation with a flow confirmation study (FCS) using fluorescence fluoroscopy or digital subtraction angiography should be performed. Evaluations of mechanical complications related to CVP of the chest wall using FCS performed via the subclavian vein have been reported. However, the delayed complications of a CVP placed in the upper arm have not been sufficiently evaluated in a large population. We evaluated the effectiveness of FCS of CVPs implanted following percutaneous cannulation of the subclavian (chest wall group) or brachial (upper arm group) vein. METHODS: A CVP was implanted in patients with advanced cancer requiring chemotherapy. FCS was performed if there were complaints suggestive of CVP dysfunction when initiating chemotherapy. RESULTS: CVPs were placed in the brachial vein in 390 patients and in the subclavian vein in 800 patients. FCS was performed in 26/390 (6.7%) patients in the upper arm group and 40/800 (5.0%) patients in the chest wall group. The clinical characteristics of the patients were similar in both groups. The duration of CVP implantation until FCS was significantly shorter in the upper arm group (136 ± 96.6 vs. 284 ± 260, p = 0.022). After FCS, the incidence of CVP removal/reimplantation being deemed unnecessary was higher in the upper arm group (21/26 [80.8%] vs. 26/40 [65.0%], p = 0.27). In the upper arm group, no cases of catheter kinking or catheter-related injury were observed, and the incidence of temporary obstruction because of blood clots that could be continued using CVP was significantly higher than that in the chest wall group (10/26 [38.5%] vs. 4/40 [10.0%], p = 0.012). CONCLUSIONS: FCS was effective in evaluating CVP system-related mechanical complications and deciding whether removal and reimplantation were required in both groups.

Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms.

BACKGROUND: The precise etiology of rotator cuff disease is unknown, but prior evidence suggests a role for genetic factors. Limited data exist identifying specific genes associated with rotator cuff tearing. The purpose of this study was to identify specific genes or genetic variants associated with rotator cuff tearing by a genome-wide association study with an independent set of rotator cuff tear cases. MATERIALS AND METHODS: A set of 311 full-thickness rotator cuff tear cases genotyped on the Illumina 5M single-nucleotide polymorphism (SNP) platform were used in a genome-wide association study with 2641 genetically matched white population controls available from the Illumina iControls database. Tests of association were performed with GEMMA software at 257,558 SNPs that compose the intersection of Illumina SNP platforms and that passed general quality control metrics. SNPs were considered significant if P < 1.94 × 10(-7) (Bonferroni correction: 0.05/257,558). RESULTS: Tests of association revealed 2 significantly associated SNPs, one occurring in SAP30BP (rs820218; P = 3.8E-9) on chromosome 17q25 and another occurring in SASH1 (rs12527089; P = 1.9E-7) on chromosome 6q24. CONCLUSIONS: This study represents the first attempt to identify genetic factors influencing rotator cuff tearing by a genome-wide association study using a dense/complete set of SNPs. Two SNPs were significantly associated with rotator cuff tearing, residing in SAP30BP on chromosome 17 and SASH1 on chromosome 6. Both genes are associated with the cellular process of apoptosis. Identification of potential genes or genetic variants associated with rotator cuff tearing may help in identifying individuals at risk for the development of rotator cuff tearing.

Significant association of full-thickness rotator cuff tears and estrogen-related receptor-ß (ESRRB).

BACKGROUND: The precise etiology of rotator cuff disease is unknown, but prior evidence suggests a role for genetic factors. Variants of estrogen-related receptor-ß (ESRRB) have been previously associated with rotator cuff disease. The purpose of the present study was to confirm the association between multiple candidate genes, including ESRRB, and rotator cuff disease in an independent set of patients with rotator cuff tear. MATERIALS AND METHODS: The Illumina 5M (Illumina Inc, San Diego, CA, USA) single nucleotide polymorphism (SNP) platform was used to genotype 175 patients with rotator cuff tear. Genotypes were used to select a set of 2595 genetically matched Caucasian controls available from the Illumina iControls database. Tests of association were performed with Genome-wide Efficient Mixed Model Association (GEMMA) software at 69 SNPs that fell within 20 kb of 6 candidate genes (DEFB1, DENND2C, ESRRB, FGF3, FGF10, and FGFR1). RESULTS: Tests of association revealed 1 significantly associated SNP occurring in ESRRB (rs17583842; P = 4.4E-4). Another SNP within ESRRB (rs7157192) had a nominal P value of 7.8E-3. FastPHASE software estimated 2 frequent haplotypes among 54 individuals who carried both risk alleles at these 2 SNPs. The first haplotype had a frequency of 13.9% (n = 15) in risk-allele carriers and only 2.2% in controls (odds ratio, 6.9; 95% confidence interval, 3.9-2.2). The second haplotype had a frequency of 12.9% in risk-allele carriers and only 2.7% in controls (odds ratio, 5.3; 95% confidence interval, 3.0-9.5). CONCLUSIONS: The significant association and the presence of high-risk haplotypes identified in the ESRRB gene confirm the association of variants in ESRRB and rotator cuff disease.

Confirmation and fine-mapping of clinical mastitis and somatic cell score QTL in Nordic Holstein cattle.

A genome-wide association study of 2098 progeny-tested Nordic Holstein bulls genotyped for 36 387 SNPs on 29 autosomes was conducted to confirm and fine-map quantitative trait loci (QTL) for mastitis traits identified earlier using linkage analysis with sparse microsatellite markers in the same population. We used linear mixed model analysis where a polygenic genetic effect was fitted as a random effect and single SNPs were successively included as fixed effects in the model. We detected 143 SNP-by-trait significant associations (P < 0.0001) on 20 chromosomes affecting mastitis-related traits. Among them, 21 SNP-by-trait combinations exceeded the genome-wide significant threshold. For 12 chromosomes, both the present association study and the previous linkage study detected QTL, and of these, six were in the same chromosomal locations. Strong associations of SNPs with mastitis traits were observed on bovine autosomes 6, 13, 14 and 20. Possible candidate genes for these QTL were identified. Identification of SNPs in linkage disequilibrium with QTL will enable marker-based selection for mastitis resistance. The candidate genes identified should be further studied to detect candidate polymorphisms underlying these QTL.

Efficacy confirmation study of aceneuramic acid administration for GNE myopathy in Japan.

BACKGROUND: A rare muscle disease, GNE myopathy is caused by mutations in the GNE gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression. METHODS: We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored. RESULTS: A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (- 0.115 kg) was numerically smaller as compared with placebo (- 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (- 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed. CONCLUSIONS: The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT04671472).

Revisiting the adequacy of infection criteria recommended in VICH GL 7 for anthelmintic effectiveness studies: Retrospective simulations.

Studies conducted to support registration or approval of veterinary anthelmintics generally follow study design recommendations provided by the VICH (International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products), "Efficacy of Anthelmintics: General Requirements" (VICH GL7). For dose confirmation studies, VICH GL7 provides recommendations for determining that the control animals had an adequate infection "to permit the appropriate standards of efficacy to be met with acceptable statistical and biological certitude/confidence." In the simulation studies described in this report, we investigated the performance of one method, the statistical criterion given in Section 4.5 of VICH GL7, for evaluating the adequacy of infection in anthelmintic studies, in combination with the conventional criterion of a minimum of six adequately infected animals. We conducted numerical simulations, based on parasite data from previously conducted dose confirmation studies in dogs and cattle, to investigate how the statistical criterion impacts adequacy of infection determinations when used with the conventional criterion at various sample sizes. Simulation studies in common nematode species in both dogs and cattle indicated that under certain circumstances the statistical criterion can guard against overinterpreting the evaluation of adequacy of infection as sample size is increased. However, the statistical criterion may be overly restrictive for samples with adequate infection but containing multiple zero parasite counts and adding it to the conventional criterion does not provide any additional benefit when the sample contains no zero counts. It is important for investigators designing efficacy studies to understand the potential impact this criterion may have when establishing adequacy of infection criteria in study protocols.