Cryptic Genomic Rearrangements in Three Patients with 46,XY Disorders of Sex Development

Background

46,XY disorders of sex development (46,XY DSD) are genetically heterogeneous conditions. Recently, a few submicroscopic genomic rearrangements have been reported as novel genetic causes of 46,XY DSD.

Methodology/Principal Findings

To clarify the role of cryptic rearrangements in the development of 46,XY DSD, we performed array-based comparative genomic hybridization analysis for 24 genetic males with genital abnormalities. Heterozygous submicroscopic deletions were identified in three cases (cases 1–3). A ∼8.5 Mb terminal deletion at 9p24.1–24.3 was detected in case 1 that presented with complete female-type external genitalia and mental retardation; a ∼2.0 Mb interstitial deletion at 20p13 was identified in case 2 with ambiguous external genitalia and short stature; and a ∼18.0 Mb interstitial deletion at 2q31.1–32 was found in case 3 with ambiguous external genitalia, mental retardation and multiple anomalies. The genital abnormalities of case 1 could be ascribed to gonadal dysgenesis caused by haploinsufficiency of DMRT1, while those of case 3 were possibly associated with perturbed organogenesis due to a deletion of the HOXD cluster. The deletion in case 2 affected 36 genes, none of which have been previously implicated in sex development.

Conclusions/Significance

The results indicate that cryptic genomic rearrangements constitute an important part of the molecular bases of 46,XY DSD and that submicroscopic deletions can lead to various types of 46,XY DSD that occur as components of contiguous gene deletion syndromes. Most importantly, our data provide a novel candidate locus for 46,XY DSD at 20p13.     

The physical map of wheat chromosome 5DS revealed gene duplications and small rearrangements

Background

The substantially large bread wheat genome, organized into highly similar three sub-genomes, renders genomic research challenging. The construction of BAC-based physical maps of individual chromosomes reduces the complexity of this allohexaploid genome, enables elucidation of gene space and evolutionary relationships, provides tools for map-based cloning, and serves as a framework for reference sequencing efforts. In this study, we constructed the first comprehensive physical map of wheat chromosome arm 5DS, thereby exploring its gene space organization and evolution.

Results

The physical map of 5DS was comprised of 164 contigs, of which 45 were organized into 21 supercontigs, covering 176 Mb with an N50 value of 2,173 kb. Fifty-eight of the contigs were larger than 1 Mb, with the largest contig spanning 6,649 kb. A total of 1,864 molecular markers were assigned to the map at a density of 10.5 markers/Mb, anchoring 100 of the 120 contigs (>5 clones) that constitute ~95 % of the cumulative length of the map. Ordering of 80 contigs along the deletion bins of chromosome arm 5DS revealed small-scale breaks in syntenic blocks. Analysis of the gene space of 5DS suggested an increasing gradient of genes organized in islands towards the telomere, with the highest gene density of 5.17 genes/Mb in the 0.67-0.78 deletion bin, 1.4 to 1.6 times that of all other bins.

Conclusions

Here, we provide a chromosome-specific view into the organization and evolution of the D genome of bread wheat, in comparison to one of its ancestors, revealing recent genome rearrangements. The high-quality physical map constructed in this study paves the way for the assembly of a reference sequence, from which breeding efforts will greatly benefit.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1641-y) contains supplementary material, which is available to authorized users.     

A genome-wide association analysis for porcine serum lipid traits reveals the existence of age-specific genetic determinants

Background

The genetic determinism of blood lipid concentrations, the main risk factor for atherosclerosis, is practically unknown in species other than human and mouse. Even in model organisms, little is known about how the genetic determinants of lipid traits are modulated by age-specific factors. To gain new insights into this issue, we have carried out a genome-wide association study (GWAS) for cholesterol (CHOL), triglyceride (TRIG) and low (LDL) and high (HDL) density lipoprotein concentrations measured in Duroc pigs at two time points (45 and 190 days).

Results

Analysis of data with mixed-model methods (EMMAX, GEMMA, GenABEL) and PLINK showed a low positional concordance between trait-associated regions (TARs) for serum lipids at 45 and 190 days. Besides, the proportion of phenotypic variance explained by SNPs at these two time points was also substantially different. The four analyses consistently detected two regions on SSC3 (124 Mb, CHOL and LDL at 190 days) and SSC6 (135 Mb, CHOL and TRIG at 190 days) with highly significant effects on the porcine blood lipid profile. Moreover, we have found that SNP variation within SSC3, SSC6, SSC10, SSC13 and SSC16 TARs is associated with the expression of several genes mapping to other chromosomes and related to lipid metabolism.

Conclusions

Our data demonstrate that the effects of genomic determinants influencing lipid concentrations in pigs, as well as the amount of phenotypic variance they explain, are influenced by age-related factors.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-758) contains supplementary material, which is available to authorized users.     

Genome Rearrangements Detected by SNP Microarrays in Individuals with Intellectual Disability Referred with Possible Williams Syndrome

Background

Intellectual disability (ID) affects 2–3% of the population and may occur with or without multiple congenital anomalies (MCA) or other medical conditions. Established genetic syndromes and visible chromosome abnormalities account for a substantial percentage of ID diagnoses, although for ∼50% the molecular etiology is unknown. Individuals with features suggestive of various syndromes but lacking their associated genetic anomalies pose a formidable clinical challenge. With the advent of microarray techniques, submicroscopic genome alterations not associated with known syndromes are emerging as a significant cause of ID and MCA.

Methodology/Principal Findings

High-density SNP microarrays were used to determine genome wide copy number in 42 individuals: 7 with confirmed alterations in the WS region but atypical clinical phenotypes, 31 with ID and/or MCA, and 4 controls. One individual from the first group had the most telomeric gene in the WS critical region deleted along with 2 Mb of flanking sequence. A second person had the classic WS deletion and a rearrangement on chromosome 5p within the Cri du Chat syndrome (OMIM:123450) region. Six individuals from the ID/MCA group had large rearrangements (3 deletions, 3 duplications), one of whom had a large inversion associated with a deletion that was not detected by the SNP arrays.

Conclusions/Significance

Combining SNP microarray analyses and qPCR allowed us to clone and sequence 21 deletion breakpoints in individuals with atypical deletions in the WS region and/or ID or MCA. Comparison of these breakpoints to databases of genomic variation revealed that 52% occurred in regions harboring structural variants in the general population. For two probands the genomic alterations were flanked by segmental duplications, which frequently mediate recurrent genome rearrangements; these may represent new genomic disorders. While SNP arrays and related technologies can identify potentially pathogenic deletions and duplications, obtaining sequence information from the breakpoints frequently provides additional information.     

Homologues of potato chromosome 5 show variable collinearity in the euchromatin,but dramatic absence of sequence similarity in the pericentromeric heterochromatin

Background

In flowering plants it has been shown that de novo genome assemblies of different species and genera show a significant drop in the proportion of alignable sequence. Within a plant species, however, it is assumed that different haplotypes of the same chromosome align well. In this paper we have compared three de novo assemblies of potato chromosome 5 and report on the sequence variation and the proportion of sequence that can be aligned.

Results

For the diploid potato clone RH89-039-16 (RH) we produced two linkage phase controlled and haplotype-specific assemblies of chromosome 5 based on BAC-by-BAC sequencing, which were aligned to each other and compared to the 52 Mb chromosome 5 reference sequence of the doubled monoploid clone DM 1–3 516 R44 (DM). We identified 17.0 Mb of non-redundant sequence scaffolds derived from euchromatic regions of RH and 38.4 Mb from the pericentromeric heterochromatin. For 32.7 Mb of the RH sequences the correct position and order on chromosome 5 was determined, using genetic markers, fluorescence in situ hybridisation and alignment to the DM reference genome. This ordered fraction of the RH sequences is situated in the euchromatic arms and in the heterochromatin borders. In the euchromatic regions, the sequence collinearity between the three chromosomal homologs is good, but interruption of collinearity occurs at nine gene clusters. Towards and into the heterochromatin borders, absence of collinearity due to structural variation was more extensive and was caused by hemizygous and poorly aligning regions of up to 450 kb in length. In the most central heterochromatin, a total of 22.7 Mb sequence from both RH haplotypes remained unordered. These RH sequences have very few syntenic regions and represent a non-alignable region between the RH and DM heterochromatin haplotypes of chromosome 5.

Conclusions

Our results show that among homologous potato chromosomes large regions are present with dramatic loss of sequence collinearity. This stresses the need for more de novo reference assemblies in order to capture genome diversity in this crop. The discovery of three highly diverged pericentric heterochromatin haplotypes within one species is a novelty in plant genome analysis. The possible origin and cytogenetic implication of this heterochromatin haplotype diversity are discussed.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1578-1) contains supplementary material, which is available to authorized users.     

CCR5Δ32 Genotypes in a German HIV-1 Seroconverter Cohort and Report of HIV-1 Infection in a CCR5Δ32 Homozygous Individual

Background

Homozygosity (Δ32/Δ32) for the 32 bp deletion in the chemokine receptor 5 (CCR5) gene is associated with strong resistance against HIV infection. Heterozygosity is associated with protection of HIV-1 disease progression.

Methodology/Principal Findings

We genotyped a population of 737 HIV-positive adults and 463 healthy controls for the CCR5Δ32 deletion and found heterozygous frequencies of 16.2% (HIV-negative) and 17.5% (HIV-positive) among Caucasian individuals. Analysis of CCR5Δ32 influence on disease progression showed notably lower viral setpoints and a longer time to a CD4 count of <200 µl⁻¹ in seroconverters heterozygous for the deletion. Furthermore, we identified one HIV-positive man homozygous for the Δ32 deletion.

Conclusions/Significance

The protective effect of CCR5 Δ32 heterozygosity is confimed in a large cohort of German seroconverters. The HIV-infected CCR5 Δ32 homozygous individual, however, displays extremely rapid disease progression. This is the 12th case of HIV-infection in this genotype described worldwide.     

Unintended irradiation of internal mammary chain – Is that enough?

Aim

To evaluate the unintentional coverage of the internal mammary chain (IMC) with tangential fields irradiation to the breast, and its relation with the type of surgery employed.

Background

The dose distribution in regions adjacent to the treatment targets (mammary gland or chest wall), with incidental irradiation of the IMC, could translate into clinical benefit, due to the proximity of these regions.

Materials and methods

One hundred and twelve consecutive conformal radiotherapy plans were correlating the average dose to the IMC with the type of surgery employed, the extent of disease and the irradiation techniques.

Results

The mean doses to IMC after modified radical mastectomy (MRM), modified radical mastectomy with immediate reconstruction (MRM + R), and breast conservative surgery (BCS) were 30.34 Gy, 30.26 Gy, and 18.67 Gy, respectively. Significant differences were identified between patients who underwent MRM or MRM + R over BCS (p = 0.01 and 0.003, respectively), but not between MRM and MRM + R (p = 0.88). Mean doses to IMC were greater in patients with T3–T4 tumors when compared with more initial stages (≤T2) (p = 0.0096). The lymph node involvement also correlated with higher average doses to IMC (node positive: 26.1 Gy × node negative: 17.8 Gy, p = 0.0017).

Conclusions

The moderate dose level to the IMC in the unintentional irradiation scenario seems to be insufficient to treat the subclinical disease, although it could have an impact in patients undergoing mastectomy.     

Large-effect pleiotropic or closely linked QTL segregate within and across ten US cattle breeds

Background

The availability of high-density SNP assays including the BovineSNP50 (50 K) enables the identification of novel quantitative trait loci (QTL) and improvement of the resolution of the locations of previously mapped QTL. We performed a series of genome-wide association studies (GWAS) using 50 K genotypes scored in 18,274 animals from 10 US beef cattle breeds with observations for twelve body weights, calving ease and carcass traits.

Results

A total of 159 large-effects QTL (defined as 1-Mb genome windows explaining more than 1% of additive genetic variance) were identified. In general, more QTL were identified in analyses with bigger sample sizes. Four large-effect pleiotropic or closely linked QTLs located on BTA6 at 37–42 Mb (primarily at 38 Mb), on BTA7 at 93 Mb, on BTA14 at 23–26 Mb (primarily at 25 Mb) and on BTA20 at 4 Mb were identified in more than one breed. Several breed-specific large-effect pleiotropic or closely linked QTL were also identified. Some identified QTL regions harbor genes known to have large effects on a variety of traits in cattle such as PLAG1 and MSTN and others harbor promising candidate genes including NCAPG, ARRDC3, ERGIC1, SH3PXD2B, HMGA2, MSRB3, LEMD3, TIGAR, SEPT7, and KIRREL3. Gene ontology analysis revealed that genes involved in ossification and in adipose tissue development were over-represented in the identified pleiotropic QTL. Also, the MAPK signaling pathway was identified as a common pathway affected by the genes located near the pleiotropic QTL.

Conclusions

This largest GWAS ever performed in beef cattle, led us to discover several novel across-breed and breed-specific large-effect pleiotropic QTL that cumulatively account for a significant percentage of additive genetic variance (e.g. more than a third of additive genetic variance of birth and mature weights; and calving ease direct in Hereford). These results will improve our understanding of the biology of growth and body composition in cattle.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-442) contains supplementary material, which is available to authorized users.     

Unraveling the effect of genomic structural changes in the rhesus macaque - implications for the adaptive role of inversions

Background

By reshuffling genomes, structural genomic reorganizations provide genetic variation on which natural selection can work. Understanding the mechanisms underlying this process has been a long-standing question in evolutionary biology. In this context, our purpose in this study is to characterize the genomic regions involved in structural rearrangements between human and macaque genomes and determine their influence on meiotic recombination as a way to explore the adaptive role of genome shuffling in mammalian evolution.

Results

We first constructed a highly refined map of the structural rearrangements and evolutionary breakpoint regions in the human and rhesus macaque genomes based on orthologous genes and whole-genome sequence alignments. Using two different algorithms, we refined the genomic position of known rearrangements previously reported by cytogenetic approaches and described new putative micro-rearrangements (inversions and indels) in both genomes. A detailed analysis of the rhesus macaque genome showed that evolutionary breakpoints are in gene-rich regions, being enriched in GO terms related to immune system. We also identified defense-response genes within a chromosome inversion fixed in the macaque lineage, underlying the relevance of structural genomic changes in evolutionary and/or adaptation processes. Moreover, by combining in silico and experimental approaches, we studied the recombination pattern of specific chromosomes that have suffered rearrangements between human and macaque lineages.

Conclusions

Our data suggest that adaptive alleles – in this case, genes involved in the immune response – might have been favored by genome rearrangements in the macaque lineage.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-530) contains supplementary material, which is available to authorized users.     

Mapping in the era of sequencing: high density genotyping and its application for mapping TYLCV resistance in Solanum pimpinellifolium

Background

A RIL population between Solanum lycopersicum cv. Moneymaker and S. pimpinellifolium G1.1554 was genotyped with a custom made SNP array. Additionally, a subset of the lines was genotyped by sequencing (GBS).

Results

A total of 1974 polymorphic SNPs were selected to develop a linkage map of 715 unique genetic loci. We generated plots for visualizing the recombination patterns of the population relating physical and genetic positions along the genome.This linkage map was used to identify two QTLs for TYLCV resistance which contained favourable alleles derived from S. pimpinellifolium. Further GBS was used to saturate regions of interest, and the mapping resolution of the two QTLs was improved. The analysis showed highest significance on Chromosome 11 close to the region of 51.3 Mb (qTy-p11) and another on Chromosome 3 near 46.5 Mb (qTy-p3). Furthermore, we explored the population using untargeted metabolic profiling, and the most significant differences between susceptible and resistant plants were mainly associated with sucrose and flavonoid glycosides.

Conclusions

The SNP information obtained from an array allowed a first QTL screening of our RIL population. With additional SNP data of a RILs subset, obtained through GBS, we were able to perform an in silico mapping improvement to further confirm regions associated with our trait of interest. With the combination of different ~ omics platforms we provide valuable insight into the genetics of S. pimpinellifolium-derived TYLCV resistance.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-1152) contains supplementary material, which is available to authorized users.     

Reliability and Validity of the Multimedia Activity Recall in Children and Adults (MARCA) in People with Chronic Obstructive Pulmonary Disease

Objective

To determine the reliability and validity of the Multimedia Activity Recall for Children and Adults (MARCA) in people with chronic obstructive pulmonary disease (COPD).

Design

People with COPD and their carers completed the Multimedia Activity Recall for Children and Adults (MARCA) for four, 24-hour periods (including test-retest of 2 days) while wearing a triaxial accelerometer (Actigraph GT3X+®), a multi-sensor armband (Sensewear Pro3®) and a pedometer (New Lifestyles 1000®).

Setting

Self reported activity recalls (MARCA) and objective activity monitoring (Accelerometry) were recorded under free-living conditions.

Participants

24 couples were included in the analysis (COPD; age 74.4±7.9 yrs, FEV₁ 54±13% Carer; age 69.6±10.9 yrs, FEV₁ 99±24%).

Interventions

Not applicable.

Main Outcome Measure(s)

Test-retest reliability was compared for MARCA activity domains and different energy expenditure zones. Validity was assessed between MARCA-derived physical activity level (in metabolic equivalent of task (MET) per minute), duration of moderate to vigorous physical activity (min) and related data from the objective measurement devices. Analysis included intra-class correlation coefficients (ICC), Bland-Altman analyses, paired t-tests (p) and Spearman''s rank correlation coefficients (r_s).

Results

Reliability between occasions of recall for all activity domains was uniformly high, with test-retest correlations consistently >0.9. Validity correlations were moderate to strong (r_s = 0.43–0.80) across all comparisons. The MARCA yields comparable PAL estimates and slightly higher moderate to vigorous physical activity (MVPA) estimates.

Conclusion

In older adults with chronic illness, the MARCA is a valid and reliable tool for capturing not only the time and energy expenditure associated with physical and sedentary activities but also information on the types of activities.     

Genetic Variants in Meiotic Program Initiation Pathway Genes Are Associated with Spermatogenic Impairment in a Han Chinese Population

Background

The meiotic program initiation pathway genes (CYP26B1, NANOS1 and STRA8) have been proposed to play key roles in spermatogenesis.

Objective

To elucidate the exact role of the genetic variants of the meiosis initiation genes in spermatogenesis, we genotyped the potential functional genetic variants of CYP26B1, NANOS1 and STRA8 genes, and evaluated their effects on spermatogenesis in our study population.

Design, Setting, and Participants

In this study, all subjects were volunteers from the affiliated hospitals of Nanjing Medical University between March 2004 and July 2009 (NJMU Infertile Study). Total 719 idiopathic infertile cases were recruited and divided into three groups according to WHO semen parameters: 201 azoospermia patients (no sperm in the ejaculate even after centrifugation), 155 oligozoospermia patients (sperm counts <20×10⁶/ml) and 363 infertility/normozoospermia subjects (sperm counts >20×10⁶/ml). The control group consisted of 383 subjects with normal semen parameters, all of which had fathered at least one child without assisted reproductive technologies.

Measurements

Eight single nucleotide polymorphisms (SNPs) in CYP26B1, NANOS1 and STRA8 genes were determined by TaqMan allelic discrimination assay in 719 idiopathic infertile men and 383 healthy controls.

Results and Limitations

The genetic variant rs10269148 of STRA8 gene showed higher risk of spermatogenic impairment in the groups of abnormospermia (including azoospermia subgroup and oligozoospermia subgroup) and azoospermia than the controls with odds ratios and 95% confidence intervals of 2.52 (1.29–4.94) and 2.92 (1.41–6.06), respectively (P = 0.006, 0.002 respective). Notably, larger sample size studies and in vivo or in vitro functional studies are needed to substantiate the biological roles of these variants.

Conclusions

Our results provided epidemiological evidence supporting the involvement of genetic polymorphisms of the meiotic program initiation genes in modifying the risk of azoospermia and oligozoospermia in a Han-Chinese population.     

A genome-wide association study of limb bone length using a Large White?×?Minzhu intercross population

Background

In pig, limb bone length influences ham yield and body height to a great extent and has important economic implications for pig industry. In this study, an intercross population was constructed between the indigenous Chinese Minzhu pig breed and the western commercial Large White pig breed to examine the genetic basis for variation in limb bone length. The aim of this study was to detect potential genetic variants associated with porcine limb bone length.

Methods

A total of 571 F2 individuals from a Large White and Minzhu intercross population were genotyped using the Illumina PorcineSNP60K Beadchip, and phenotyped for femur length (FL), humerus length (HL), hipbone length (HIPL), scapula length (SL), tibia length (TL), and ulna length (UL). A genome-wide association study was performed by applying the previously reported approach of genome-wide rapid association using mixed model and regression. Statistical significance of the associations was based on Bonferroni-corrected P-values.

Results

A total of 39 significant SNPs were mapped to a 11.93 Mb long region on pig chromosome 7 (SSC7). Linkage analysis of these significant SNPs revealed three haplotype blocks of 495 kb, 376 kb and 492 kb, respectively, in the 11.93 Mb region. Annotation based on the pig reference genome identified 15 genes that were located near or contained the significant SNPs in these linkage disequilibrium intervals. Conditioned analysis revealed that four SNPs, one on SSC2 and three on SSC4, showed significant associations with SL and HL, respectively.

Conclusions

Analysis of the 15 annotated genes that were identified in these three haplotype blocks indicated that HMGA1 and PPARD, which are expressed in limbs and influence chondrocyte cell growth and differentiation, could be considered as relevant biological candidates for limb bone length in pig, with potential applications in breeding programs. Our results may also be useful for the study of the mechanisms that underlie human limb length and body height.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-014-0056-6) contains supplementary material, which is available to authorized users.     

Hawthorne Effect with Transient Behavioral and Biochemical Changes in a Randomized Controlled Sleep Extension Trial of Chronically Short-Sleeping Obese Adults: Implications for the Design and Interpretation of Clinical Studies

Objective

To evaluate the effects of study participation per se at the beginning of a sleep extension trial between screening, randomization, and the run-in visit.

Design

Subjects were screened, returned for randomization (Comparison vs. Intervention) after 81 days (median), and attended run-in visit 121 days later.

Setting

Outpatient.

Patients

Obese (N = 125; M/F, 30/95; Blacks/Whites/Other, N = 73/44/8), mean weight 107.6±19.7 kg, <6.5 h sleep/night.

Intervention

Non-pharmacological sleep extension.

Measurements

Sleep duration (diaries and actigraphy watch), sleep quality (Pittsburgh Sleep Quality Index), daily sleepiness (Epworth Sleepiness Scale), fasting glucose, insulin and lipids.

Results

Prior to any intervention, marked improvements occurred between screening and randomization. Sleep duration increased (diaries: 357.4 ±51.2 vs. 388.1±48.6 min/night; mean±SD; P<0.001 screening vs. randomization; actigraphy: 344.3 ±41.9 vs. 358.6±48.2 min/night; P<0.001) sleep quality improved (9.1±3.2 vs. 8.2±3.0 PSQI score; P<0.001), sleepiness tended to improve (8.9±4.6 vs. 8.3±4.5 ESS score; P = 0.06), insulin resistance decreased (0.327±0.038 vs. 0.351±0.045; Quicki index; P<0.001), and lipids improved, except for HDL-C. Abnormal fasting glucose (25% vs. 11%; P = 0.007), and metabolic syndrome (42% vs. 29%; P = 0.007) both decreased. In absence of intervention, the earlier metabolic improvements disappeared at the run-in visit.

Limitations

Relatively small sample size.

Conclusions

Improvements in biochemical and behavioral parameters between screening and randomization changed the “true” study baseline, thereby potentially affecting outcome. While regression to the mean and placebo effect were considered, these findings are most consistent with the “Hawthorne effect”, according to which behavior measured in the setting of an experimental study changes in response to the attention received from study investigators. This is the first time that biochemical changes were documented with respect to the Hawthorne effect. The findings have implications for the design and conduct of clinical research.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00261898","term_id":"NCT00261898"}}NCT00261898.     

Normoxic polymer gel dosimetry using less toxic monomer of N-isopropyl acrylamide and X-ray computed tomography for radiation therapy applications

Background

Polymer gel dosimetry has been used extensively in radiation therapy for its capability in depicting a three dimensional view of absorbed dose distribution. However, more studies are required to find less toxic and more efficient polymers for application in radiotherapy dosimetry.

Aim

The purpose of this work was to evaluate the N-isopropyl acrylamide (NIPAM) gel dosimetric characteristics and optimize the protocol for X-ray computed tomography (CT) imaging of gel dosimeters for radiation therapy application.

Material and methods

A polymer gel dosimeter based on NIPAM monomer was prepared and irradiated with ⁶⁰Co photons. The CT number changes following irradiation were extracted from CT images obtained with different sets of imaging parameters.

Results

The results showed the dose sensitivity of ΔN_CT (H) = 0.282 ± 0.018 (H Gy⁻¹) for NIPAM gel dosimeter. The optimized set of imaging exposure parameters was 120 kV_p and 200 mA with the 10 mm slice thickness. Results of the depth dose measurement with gel dosimeter showed a great discrepancy with the actual depth dose data.

Conclusion

According to the current study, NIPAM-based gel dosimetry with X-ray CT imaging needs more technical development and formulation refinement to be used for radiation therapy application.     

Evaluation of the Cost Effectiveness of Vesico-Amniotic Shunting in the Management of Congenital Lower Urinary Tract Obstruction (Based on Data from the PLUTO Trial)

Objective

To determine the cost-effectiveness of in-utero percutaneous Vesico Amniotic Shunt (VAS) in the management of fetal lower urinary tract obstruction (LUTO)

Design

Model based economic analysis using data from the randomised controlled arm of the PLUTO (percutaneous vesico-amniotic shunting for lower urinary tract obstruction) trial.

Setting

Fetal medicine departments in United Kingdom, Ireland and Netherlands.

Population or Sample

Pregnant women with a male, singleton fetus with LUTO.

Methods

Costs and outcomes were prospectively collected in the trial; three separate base case analyses were performed using the intention to treat (ITT), per protocol and uniform prior methods. Deterministic and probabilistic sensitivity analyses were performed to explore data uncertainty.

Main Outcome Measures

Survival at 28 days, 1 year and disease free survival at 1 year.

Results

VAS was more expensive but appeared to result in higher rates of survival compared with conservative management in patients with LUTO. Using ITT analysis the incremental cost effectiveness ratios based on outcomes of survival at 28 days, 1 year, or 1 morbidity-free year on the VAS arm were £15,506, £15,545, and £43,932, respectively.

Conclusions

VAS is a more expensive option compared to the conservative approach in the management of individuals with LUTO. Data from the RCT suggest that VAS improves neonatal survival but does not result in significant improvements in morbidity. Our analysis concludes that VAS is not likely to be cost effective in the management of these patients given the NICE (National Institute of Health and Clinical Excellence) cost threshold of £20,000 per QALY.