Limited data exist regarding how medications for pediatric use can be developed to minimize medication errors. The integrase inhibitor raltegravir was developed for use in neonates (≥2 kg). ...Anticipating that neonatal administration would be performed primarily by mothers with varying degrees of health literacy, a health literate, patient-focused, iterative process was conducted to update/redesign the raltegravir granules for oral suspension pediatric kit and instructions for use (IFU) for neonatal use to be ready for regulatory submission.
Prototypes of an updated/redesigned raltegravir IFU were systematically assessed through multi-stage, iterative testing and evaluation involving untrained lay individuals with varying levels of health literacy, healthcare professionals and health literacy experts.
This iterative process resulted in numerous refinements to the IFU and kit, including wording, layout, presentation, colored syringes and additional instructional steps. The revised raltegravir pediatric kit and IFU (to include neonatal dosing) were approved by the US Food and Drug Administration in 2017 and the European Union in 2018. No reported medication errors related to IFU utilization had been reported as of March 2021, reflecting >3 years of commercial use worldwide.
This patient-focused process produced health literate instructions for preparing and administering an antiretroviral for neonatal use with complex dosing requirements. Testing demonstrated that lay users with a range of health literacy levels were able to accurately mix, measure and administer the product. This process demonstrates how a neonatal medication can be optimized for use through collaboration between the infectious disease expert community and a manufacturer.
The aim of this study was to determine the biodistribution and tumor targeting ability of (14)C-labeled 3-bromopyruvate ((14)C3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In ...addition, we evaluated the effects of (14)C3-BrPA on tumor and healthy tissue glucose metabolism by determining (18)F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM (14)C3-BrPA i.a., 1.75 mM (14)C3-BrPA i.v., 20 mM (14)C3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM (14)C3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of (14)C3-BrPA was 1.8 +/- 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of (14)C3-BrPA was 0.03 +/- 0.01% ID/g. After i.a. administration of (14)C3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of (14)C3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit.
Identification of resistance (R) genes to Phytophthora infestans is an essential step in molecular breeding of potato. We identified three specific R genes segregating in a diploid mapping ...population. One of the R genes is located on chromosome 4 and proved phenotypically indistinguishable from the Solanum demissum-derived R2, although S. demissum is not directly involved in the pedigree of the population. By bulked segregant analysis combined with a resistance assay, a genetic linkage map of the R2-like locus was constructed with 30 coupling and 23 repulsion phase AFLP markers. Two markers flanking the R2-like locus were applied to screen an extended population of 1,586 offspring. About 103 recombinants were selected, and an accurate high-resolution map was constructed. The R2-like resistance was localized in a 0.4 cM interval and was found co-segregating with four AFLP markers, which can be used to isolate the R2-like gene by map-based gene cloning. By analyzing race-specificity and R gene-specific molecular markers, we also found that an R1-like gene and an additional unknown R gene are segregating in the population.
To assess the value of functional magnetic resonance (MR) imaging in the evaluation of early tumor response after transarterial chemoembolization (TACE) for metastatic breast cancer and to compare ...tumor response based on functional MR imaging versus traditional assessment based on iodized oil deposition, tumor size, and tumor enhancement.
For 14 patients with metastatic breast cancer, MR imaging studies before and after TACE were evaluated. Diffusion and contrast medium-enhanced MR imaging was performed on a 1.5-T unit. Parameters evaluated included change in tumor size, enhancement, and apparent diffusion coefficient (ADC) values. Median survival was also calculated in the entire cohort.
A total number of 27 lesions were evaluated, with a mean diameter of 5.5 cm. Although mean tumor size decreased by 18% after treatment, no tumors met the Response Evaluation Criteria In Solid Tumors (RECIST) for complete response (ie, complete disappearance of target lesions) and only seven of 27 met RECIST for partial response (ie, >30% decrease in target lesion size). After treatment, decrease of tumor enhancement in the arterial (32%) and portal venous (39%) phases was statistically significant (P < .0001). Mean tumor ADC increased by 27% (P < .0001) after TACE, whereas ADC remained unchanged in nontumorous liver, spleen, and kidney. Median survival was 25 months for the entire cohort.
In patients with breast cancer and liver metastases who were treated with TACE, although changes in tumor size were small, significant early changes in the treated lesions occurred on contrast medium-enhanced and functional MR imaging. These include decrease in tumor enhancement and increase in tumor ADC value, which suggest increasing tumor necrosis and cell death.
Congenital infections are associated with a wide spectrum of clinical symptoms, including lenticulostriate vasculopathy (LSV).
To determine the relationship between LSV and congenital infections, as ...diagnosed by TORCH serology and viral culture for cytomegalovirus (CMV).
All neonates with LSV admitted to our neonatal intensive-care unit from 2004 to 2008 were included in the study. Results of maternal and neonatal TORCH testing were evaluated.
During the study period, cranial ultrasound scans were performed in 2,088 neonates. LSV was detected in 80 (4%) neonates. Maternal and/or neonatal serological TORCH tests were performed in 73% (58/80) of cases. None of the mothers or infants (0 of 58) had positive IgM titres for Toxoplasma, rubella, CMV or herpes simplex virus. Additional urine culture for CMV was performed in 38 neonates. None of the infants (0 of 38) had a positive CMV urine culture test.
Routinely applied efforts to diagnose congenital infections in cases presenting with LSV have a poor yield. Routine TORCH screening in neonates with LSV cases should only be regarded as mandatory once well-designed studies demonstrate a clear diagnostic benefit.
We report the generation of mice with an intact and functional copy of the 2.3-megabase human dystrophin gene (hDMD), the largest functional stretch of human DNA thus far integrated into a mouse ...chromosome. Yeast spheroplasts containing an artificial chromosome with the full-length hDMD gene were fused with mouse embryonic stem cells and were subsequently injected into mouse blastocysts to produce transgenic hDMD mice. Human-specific PCR, Southern blotting, and fluorescent in situ hybridization techniques demonstrated the intactness and stable chromosomal integration of the hDMD gene on mouse chromosome 5. Expression of the transgene was confirmed by RT-PCR and Western blotting. The tissue-specific expression pattern of the different DMD transcripts was maintained. However, the human Dp427p and Dp427m transcripts were expressed at 2-fold higher levels and human Dp427c and Dp260 transcripts were expressed at 2- and 4-fold lower levels than their endogenous counterparts. Ultimate functional proof of the hDMD transgene was obtained by crossing of hDMD mice with dystrophin-deficient mdx mice and dystrophin and utrophin-deficient mdx × Utrn-/- mice. The hDMD transgene rescued the lethal dystrophic phenotype of the mdx × Utrn-/- mice. All signs of muscular dystrophy disappeared in the rescued mice, as demonstrated by histological staining of muscle sections and gene expression profiling experiments. Currently, hDMD mice are extensively used for preclinical testing of sequence-specific therapeutics for the treatment of Duchenne muscular dystrophy. In addition, the hDMD mouse can be used to study the influence of the genomic context on deletion and recombination frequencies, genome stability, and gene expression regulation.
High levels of resistance to
Phytophthora infestans
in
Solanum
are predominantly based on the gene-for-gene interaction. Identification of hitherto unknown
R
genes is essential for future pyramiding ...approaches. This could be achieved either through classic introgression breeding or through cisgenesis and could lead to sustainable control of late blight. Here, we report on the mapping of
Rpi-cap1
and
Rpi-qum1
, two late blight
R
genes identified in the wild species
Solanum capsicibaccatum
and
Solanum circaeifolium
ssp.
quimense
, respectively, to very similar positions on the long arm of chromosome 11. Despite the difficulties encountered for marker development, a high-resolution genetic map with cleaved amplified polymorphic sequence markers was constructed. Furthermore, an
R
gene cluster-directed profiling approach led to the development of markers that closely linked to or co-segregated with the
Rpi-cap1
gene. Both
R
genes are hypothesized to be homologous to the
N
gene, a toll-interleukin1 receptor–nucleotide-binding site–leucine-rich repeat domain type of
R
gene to tobacco mosaic virus from tobacco. To confirm this hypothesis, cloning of
Rpi-cap1
and
Rpi-qum1
should be pursued. Cloning would also be instrumental to facilitate the introduction of these valuable
R
genes into potato crops using cisgenic- and marker-assisted breeding approaches.
Aims/hypothesis
High levels of circulating mannan-binding lectin (MBL) are associated with the development of diabetic nephropathy and hyperglycaemia-induced vasculopathy. Here, we aimed to assess ...the effect of glycaemic control on circulating levels of MBL and the relationship of these levels with vascular damage.
Methods
We assessed MBL levels and corresponding
MBL2
genotype, together with vascular endothelial growth factor (VEGF) levels as a marker of vascular damage, in type 1 diabetes patients with diabetic nephropathy before and after simultaneous pancreas–kidney (SPK) transplantation. We included diabetic nephropathy patients (
n
= 21), SPK patients (
n
= 37), healthy controls (
n
= 19), type 1 diabetes patients (
n
= 15) and diabetic nephropathy patients receiving only a kidney transplant (
n
= 15). Fourteen diabetic nephropathy patients were followed up for 12 months after SPK.
Results
We found elevated circulating MBL levels in diabetic nephropathy patients, and a trend towards elevated circulating MBL levels in type 1 diabetes patients, compared with healthy control individuals. MBL levels in SPK patients completely normalised and our data indicate that this predominantly occurs in patients with a polymorphism in the
MBL2
gene. By contrast, MBL levels in kidney transplant only patients remained elevated, suggesting that glycaemic control but not reversal of renal failure is associated with decreased MBL levels. In line, levels of glucose and HbA
1c
, but not creatinine levels and estimated GFR, were correlated with MBL levels. VEGF levels were associated with levels of MBL and HbA
1c
in an MBL-polymorphism-dependent manner.
Conclusions/interpretation
Taken together, circulating MBL levels are associated with diabetic nephropathy and are dependent on glycaemic control, possibly in an
MBL2
-genotype-dependent manner.
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