Pharmacokinetics and Bioequivalence of Isavuconazole Administered as Isavuconazonium Sulfate Intravenous Solution via Nasogastric Tube or Orally in Healthy Subjects.

For critically ill patients with invasive fungal infections, a nasogastric (NG) tube can be an alternative route for administration of isavuconazonium sulfate (ISAVUSULF). This was a randomized, open-label, 2-period, 2-sequence single-dose crossover study comparing single doses of 372 mg ISAVUSULF intravenous (i.v.) solution via NG tube (test formulation) to 372-mg ISAVUSULF capsules for oral administration (reference formulation) in healthy male and female subjects. A single dose of ISAVUSULF was administered under fasting conditions on day 1 of each period, with a washout of 30 days between periods. Pharmacokinetic (PK) samples were collected predose through day 21. Standard safety and tolerability assessments were conducted in each period. The analysis of variance estimate of the study population demonstrates that the isavuconazole i.v. NG tube administration geometric least-squares (LS) mean values of the observed maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration (AUClast), AUC to time infinity (AUCinf), and AUC from start of dosing to 72 h (AUC72) were 105.3%, 97.6%, 99.3%, and 97.8%, respectively, of the corresponding oral-administration values. The geometric LS mean ratio and 90% confidence intervals for the PK parameters were completely contained within the prespecified limits of 80% to 125%. There were no deaths or serious adverse events that led to the withdrawal of treatment during the study. The study met its primary endpoint of bioequivalence between the two routes of administration. Both routes of administration were well tolerated.

Clostridioides (Clostridium) difficile infection in Japanese hospitals 2008-2017: A real-world nationwide analysis of treatment pattern, incidence and testing density.

OBJECTIVE: To characterize treatment pattern, incidence and diagnosis of hospital-onset Clostridioides difficile infection (CDI) in Japan, cases were studied over a 9-year period using a large, administrative database. METHODS: This was a retrospective, cross-sectional analysis of inpatients at 320 Japanese Diagnosis-Procedure Combination (DPC) hospitals. Hospitalizations between April 2008 and March 2017 were extracted for patients aged ≥18 years. CDI was defined as CDI treatment plus CDI diagnosis or positive enzyme immunoassay (EIA) result. Endpoints included treatment (type, route, daily dose, duration), time to CDI onset from admission, and time to recurrence (rCDI) from the end of treatment. Chronological changes were reported for treatment pattern, CDI incidence and EIA testing. RESULTS: The analysis included 11,823 CDI hospitalizations, 1359 with rCDI. Overall, oral metronidazole (MNZ), oral vancomycin (VCM), and intravenous MNZ were used in 50.2%, 42.1% and 1.2% of CDI hospitalizations, respectively. From 2009 to 2017, CDI hospitalizations treated with MNZ more than doubled and VCM more than halved. Median (Q1-Q3) time to CDI and rCDI onset was 25 (11-52) days and 10 (6-17.5) days, respectively. Median treatment duration ranged from 8 to 10 days and median dose was 1 g/day for both MNZ and VCM. CDI incidence remained steady from 2010 until 2017 (0.99/10,000 patient-days) and EIA testing density doubled from 2008 to 2017 (24.46/10,000 patient-days). CONCLUSION: Oral MNZ has become the primary CDI treatment in Japanese DPC hospitals. The treatment duration and dose were aligned to the package insert. CDI diagnostic testing density increased over time, CDI incidence did not. CLINICAL TRIAL REGISTRATION NUMBER: N/A.

The effects of home-based primary care on Medicare costs at Spectrum Health/Priority Health (Grand Rapids, MI, USA) from 2012-present: a matched cohort study.

BACKGROUND: In the United States, home-based primary care (HBPC) is increasingly proposed as a means of enabling frail elders to remain at home for as long as possible, while still receiving needed medical care. However, there are relatively few studies of either the medical outcome effects or cost benefits of HBPC. In this paper, we examine medical cost and mortality outcomes for enrollees in the HBPC program offered by Spectrum Health/Priority Health (SH/PH), a not-for-profit integrated health care/health insurance system located in Grand Rapids, MI, USA. METHODS: We perform a concurrent matched cohort study. SH/PH HBPC enrollees during 2012-2014 are matched for prior costs, age, sex and comorbidities against controls selected from unenrolled insurance plan members. Twelve and twenty four-month medical costs are compared between HBPC participants and matched controls, overall and conditional on mortality status. Mortality rates of HBPC participants are studied on their own and in comparison to controls. RESULTS: At 12 and 24 months, in comparison to matched controls HBPC participants show higher ($2933) and lower ($8620) costs respectively. Relative costs and savings of HBPC participants are a function of short term increased costs upon entry into the program (enrollees who survive the first year cost $5866 more than controls); substantial savings at end-of-life (approximately $37,037 in savings relative to controls are realized); and the overall mortality of HBPC participants (mean residual lifespan is 37.75 months from the time of enrollment). We project the present value of lifetime medical cost savings due to enrollment in the HBPC program to be at least $14,336. CONCLUSIONS: The SH/PC HBPC program reduces healthcare costs while enabling frail elders to remain at home. Reduction in costs is obtained at end-of-life and is offset with a smaller initial increase in costs upon enrollment.

Randomized controlled trial of perioperative ICD management: magnet application versus reprogramming.

BACKGROUND: There are insufficient data to guide perioperative implantable cardioverter-defibrillator (ICD) management for patients undergoing surgical procedures using electrocautery. METHODS: We conducted a multicenter randomized controlled trial of patients with ICDs undergoing surgery with monopolar electrocautery. Subjects were randomized to an "Off" group (ICD therapy programmed off, then postoperatively programmed on) or a "Magnet" group (ICD therapy suspended with a magnet and no immediate postoperative ICD interrogation). Also, a registry was maintained of ICD patients with procedures within 6 inches of the ICD (all programmed off). The primary endpoint was ICD off time with secondary endpoints being caregiver handoffs and incidence of electromagnetic interference (EMI). RESULTS: All patients (n = 80) had pectoral ICDs. Subject demographics were well matched in each group, and duration of electrocautery was similar (80 minutes vs 64 minutes, P = 0.58). The mean "excess" ICD off time (ICD off time - electrocautery time) was significantly higher in the Off group than the Magnet group (115 minutes vs 28 minutes, P < 0.001). Mean number of caregiver handoffs were higher in the Off group (6.6 vs 5.5, P < 0.001). There was no EMI in any lower abdominal or lower extremity procedures. Neither group had arrhythmic events or device reset. CONCLUSION: A magnet protocol simplifies perioperative ICD management for procedures using electrocautery more than 6 inches from the ICD. This protocol results in significantly shorter time with ICD therapy off, fewer provider handoffs, no risk of inadvertently discharging patients home with ICD therapies off, and no device reset.

Improved minimum cost and maximum power two stage genome-wide association study designs.

In a two stage genome-wide association study (2S-GWAS), a sample of cases and controls is allocated into two groups, and genetic markers are analyzed sequentially with respect to these groups. For such studies, experimental design considerations have primarily focused on minimizing study cost as a function of the allocation of cases and controls to stages, subject to a constraint on the power to detect an associated marker. However, most treatments of this problem implicitly restrict the set of feasible designs to only those that allocate the same proportions of cases and controls to each stage. In this paper, we demonstrate that removing this restriction can improve the cost advantages demonstrated by previous 2S-GWAS designs by up to 40%. Additionally, we consider designs that maximize study power with respect to a cost constraint, and show that recalculated power maximizing designs can recover a substantial amount of the planned study power that might otherwise be lost if study funding is reduced. We provide open source software for calculating cost minimizing or power maximizing 2S-GWAS designs.

GLOGS: a fast and powerful method for GWAS of binary traits with risk covariates in related populations.

SUMMARY: Mixed model-based approaches to genome-wide association studies (GWAS) of binary traits in related individuals can account for non-genetic risk factors in an integrated manner. However, they are technically challenging. GLOGS (Genome-wide LOGistic mixed model/Score test) addresses such challenges with efficient statistical procedures and a parallel implementation. GLOGS has high power relative to alternative approaches as risk covariate effects increase, and can complete a GWAS in minutes. AVAILABILITY: Source code and documentation are provided at http://www.bioinformatics.org/~stanhope/GLOGS.

Occupancy modeling, maximum contig size probabilities and designing metagenomics experiments.

Mathematical aspects of coverage and gaps in genome assembly have received substantial attention by bioinformaticians. Typical problems under consideration suppose that reads can be experimentally obtained from a single genome and that the number of reads will be set to cover a large percentage of that genome at a desired depth. In metagenomics experiments genomes from multiple species are simultaneously analyzed and obtaining large numbers of reads per genome is unlikely. We propose the probability of obtaining at least one contig of a desired minimum size from each novel genome in the pool without restriction based on depth of coverage as a metric for metagenomic experimental design. We derive an approximation to the distribution of maximum contig size for single genome assemblies using relatively few reads. This approximation is verified in simulation studies and applied to a number of different metagenomic experimental design problems, ranging in difficulty from detecting a single novel genome in a pool of known species to detecting each of a random number of novel genomes collectively sized and with abundances corresponding to given distributions in a single pool.

A noncoding antisense RNA in tie-1 locus regulates tie-1 function in vivo.

Recently, messenger RNAs in eukaryotes have shown to associate with antisense (AS) transcript partners that are often referred to as long noncoding RNAs (lncRNAs) whose function is largely unknown. Here, we have identified a natural AS transcript for tyrosine kinase containing immunoglobulin and epidermal growth factor homology domain-1 (tie-1), tie-1AS lncRNA in zebrafish, mouse, and humans. In embryonic zebrafish, tie-1AS lncRNA transcript is expressed temporally and spatially in vivo with its native target, the tie-1 coding transcript and in additional locations (ear and brain). The tie-1AS lncRNA selectively binds tie-1 mRNA in vivo and regulates tie-1 transcript levels, resulting in specific defects in endothelial cell contact junctions in vivo and in vitro. The ratio of tie-1 versus tie-1AS lncRNA is altered in human vascular anomaly samples. These results directly implicate noncoding RNA-mediated transcriptional regulation of gene expression as a fundamental control mechanism for physiologic processes, such as vascular development.

Statistical use of argonaute expression and RISC assembly in microRNA target identification.

MicroRNAs (miRNAs) posttranscriptionally regulate targeted messenger RNAs (mRNAs) by inducing cleavage or otherwise repressing their translation. We address the problem of detecting m/miRNA targeting relationships in homo sapiens from microarray data by developing statistical models that are motivated by the biological mechanisms used by miRNAs. The focus of our modeling is the construction, activity, and mediation of RNA-induced silencing complexes (RISCs) competent for targeted mRNA cleavage. We demonstrate that regression models accommodating RISC abundance and controlling for other mediating factors fit the expression profiles of known target pairs substantially better than models based on m/miRNA expressions alone, and lead to verifications of computational target pair predictions that are more sensitive than those based on marginal expression levels. Because our models are fully independent of exogenous results from sequence-based computational methods, they are appropriate for use as either a primary or secondary source of information regarding m/miRNA target pair relationships, especially in conjunction with high-throughput expression studies.

MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins.

Using highly sensitive microarray-based procedures, we identified eight microRNAs (miRNAs) showing robust differential expression between 31 laser-capture-microdissected nasopharyngeal carcinomas (NPCs) and 10 normal healthy nasopharyngeal epithelial samples. In particular, miRNA mir-29c was expressed at one-fifth the levels in tumors as in normal epithelium. In NPC tumors, the lower mir-29c levels correlated with higher levels of multiple mRNAs whose 3' UTRs can bind mir-29c at target sequences conserved across many vertebrates. In cultured cells, introduction of mir-29c down-regulated these genes at the level of mRNA and inhibited expression of luciferase encoded by vectors having the 3' UTRs of these genes. Moreover, for each of several genes tested, mutating the mir-29c target sites in the 3' UTR abrogated mir-29c-induced inhibition of luciferase expression. Most of the mir-29c-targeted genes identified encode extracellular matrix proteins, including multiple collagens and laminin gamma1, that are associated with tumor cell invasiveness and metastatic potential, prominent characteristics of NPC. Thus, we identify eight miRNAs differentially expressed in NPC and demonstrate the involvement of one in regulating genes involved in metastasis.

A novel method for biodosimetry.

Accurate methods for measuring the biological effects of radiation are critical for estimating an individual's health risk from radiation exposure. We investigated the feasibility of using radiation-induced mutations in repetitive DNA sequences to measure genetic damage caused by radiation exposure. Most repetitive sequences are in non-coding regions of the genome and alterations in these loci are usually not deleterious. Thus, mutations in non-coding repetitive sequences might accumulate, providing a stable molecular record of DNA damage caused by all past exposures. To test this hypothesis, we screened repetitive DNA sequences to identify the loci most sensitive to radiation-induced mutations and then investigated whether these mutations were stable in vivo over time and after multiple exposures. Microsatellite repeat markers were identified that exhibited a linear dose response up to 1 Gy of 1 GeV/nucleon 56Fe ions and 137Cs gamma rays in mouse and human cells. Short tandem repeats on the Y chromosome and mononucleotide repeats on autosomal chromosomes exhibited significant increases in mutations at >or= 0.5 Gy of 56Fe ions with frequencies averaging 4.3-10.3 x 10(-3) mutations/locus/Gy/cell, high enough for direct detection of mutations in irradiated cells. A significant increase in radiation-induced mutations in extended mononucleotide repeats was detectible in vivo in mouse blood and cheek samples 10 and 26 weeks after radiation exposure and these mutations were additive over multiple exposures. This study demonstrates the feasibility of a novel method for biodosimetry that is applicable to humans and other species. This new approach should complement existing methods of biodosimetry and might be useful for measuring radiation exposure in circumstances that are not amenable to current methods.

Polyclonality of familial murine adenomas: analyses of mouse chimeras with low tumor multiplicity suggest short-range interactions.

In previous studies demonstrating the polyclonal structure of familial intestinal adenomas, high tumor multiplicity made it difficult to eliminate the possibility that polyclonality arose by the random collision of distinct initiated clones as opposed to some form of clonal interaction. We sought to test further the random collision hypothesis. Chimeric mice carrying the multiple intestinal neoplasia (Min) mutation of the adenomatous polyposis coli gene (Apc) and homozygous for the tumor resistance allele of the Mom1 locus were established. These chimeras also display a strong propensity for tumors of polyclonal structure, despite their markedly reduced tumor multiplicity. Considering tumor sizes and multiplicities, the observed fraction of overtly polyclonal heterotypic adenomas was significantly higher than predicted by the random collision hypothesis. This finding supports models of polyclonality involving interaction among multiple initiated clones. The extent of clonal interaction was assessed by statistical analyses that relate the observed frequency of overtly polyclonal heterotypic tumors to the geometry of the chimeric patches and the pattern of underlying crypts. These statistical calculations indicate that the familial adenomas of the Apc(Min/+) mouse may commonly form through interactions between clones as close as 1-2 crypt diameters apart.