Commissioning and implementing a Quality Assurance program for dedicated radiation oncology MRI scanners.

PURPOSE: ACR and AAPM task group's guidelines addressing commissioning for dedicated MR simulators were recently published. The goal of the current paper is to present the authors' 2-year experience regarding the commissioning and introduction of a QA program based on these guidelines and an associated automated workflow. METHODS: All mandatory commissioning tests suggested by AAPM report 284 were performed and results are reported for two MRI scanners (MAGNETOM Sola and Aera). Visual inspection, vendor clinical or service platform, third-party software, or in-house python-based code were used. Automated QA and data analysis was performed via vendor, in-house or third-party software. QATrack+ was used for QA data logging and storage. 3D geometric distortion, B0 inhomogeneity, EPI, and parallel imaging performance were evaluated. RESULTS: Contrasting with AAPM report 284 recommendations, homogeneity and RF tests were performed monthly. The QA program allowed us to detect major failures over time (shimming, gradient calibration and RF interference). Automated QA, data analysis, and logging allowed fast ACR analysis daily and monthly QA to be performed in 3 h. On the Sola, the average distortion is 1 mm for imaging radii of 250 mm or less. For radii of up to 200 mm, the maximum, average (standard deviation) distortion is 1.2  and 0.4 mm (0.3 mm). Aera values are roughly double the Sola for radii up to 200 mm. EPI geometric distortion, ghosting ratio, and long-term stability were found to be under the maximum recommended values. Parallel imaging SNR ratio was stable and close to the theoretical value (ideal g-factor). No major failures were detected during commissioning. CONCLUSION: An automated workflow and enhanced QA program allowed to automatically track machine and environmental changes over time and to detect periodic failures and errors that might otherwise have gone unnoticed. The Sola is more geometrically accurate, with a more homogenous B0 field than the Aera.

Pathological investigation of high pathogenicity avian influenza H5N8 in captive houbara bustards (Chlamydotis undulata), the United Arab Emirates 2020.

At the end of 2020, an outbreak of HPAI H5N8 was registered in captive African houbara bustards (Chlamydotis undulata) in the United Arab Emirates. In order to better understand the pathobiology of this viral infection in bustards, a comprehensive pathological characterization was performed. A total of six birds were selected for necropsy, histopathology, immunohistochemistry, RNAscope in situ hybridization and RT-qPCR and nanopore sequencing on formalin-fixed and paraffin-embedded (FFPE) tissue blocks. Gross lesions included mottled and/or hemorrhagic pancreas, spleen and liver and fibrinous deposits on air sacs and intestine. Necrotizing pancreatitis, splenitis and concurrent vasculitis, hepatitis and fibrino-heterophilic peritonitis were identified, microscopically. Viral antigens (nucleoprotein) and RNAs (matrix gene) were both detected within necro-inflammatory foci, parenchymal cells, stromal cells and endothelial cells of affected organs, including the myenteric plexus. Molecular analysis of FFPE blocks successfully detected HPAI H5N8, further confirming its involvement in the lesions observed. In conclusion, HPAI H5N8 in African houbara bustards results in hyperacute/acute forms exhibiting marked pantropism, endotheliotropism and neurotropism. In addition, our findings support the use of FFPE tissues for molecular studies of poorly characterized pathogens in exotic and endangered species, when availability of samples is limited.

Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss.

The TGFß signaling mediator SMAD4 is frequently mutated or deleted in colorectal and pancreatic cancers. SMAD4 acts as a tumor suppressor and its loss is associated with poorer patient outcomes. The purpose of this study was to find synthetic lethal interactions with SMAD4 deficiency to find novel therapeutic strategies for the treatment of patients with SMAD4-deficient colorectal or pancreatic cancers. Using pooled lentiviral single-guide RNA libraries, we conducted genome-wide loss-of-function screens in Cas9-expressing colorectal and pancreatic cancer cells harboring altered or wild-type SMAD4. The small GTPase protein RAB10 was identified and validated as a susceptibility gene in SMAD4-altered colorectal and pancreatic cancer cells. Rescue assays showed that RAB10 reintroduction reversed the antiproliferative effects of RAB10 knockout in SMAD4-negative cell lines. Further investigation is necessary to shed light on the mechanism by which RAB10 inhibition decreases cell proliferation of SMAD4-negative cells. Significance: This study identified and validated RAB10 as new synthetic lethal gene with SMAD4. This was achieved by conducting a whole-genome CRISPR screens in different colorectal and pancreatic cell lines. A future RAB10 inhibitors could correspond to a new therapeutic solution for patients with cancer with SMAD4 deletion.

Ranking parameters driving siring success during sperm competition in the North African houbara bustard.

Sperm competition is a powerful force driving the evolution of ejaculate and sperm traits. However, the outcome of sperm competition depends on many traits that extend beyond ejaculate quality. Here, we study male North African houbara bustards (Chlamydotis undulata undulata) competing for egg fertilization, after artificial insemination, with the aim to rank the importance of 14 parameters as drivers of siring success. Using a machine learning approach, we show that traits independent of male quality (i.e., insemination order, delay between insemination and egg laying) are the most important predictors of siring success. Traits describing intrinsic male quality (i.e., number of sperm in the ejaculate, mass motility index) are also positively associated with siring success, but their contribution to explaining the outcome of sperm competition is much lower than for insemination order. Overall, this analysis shows that males mating at the last position in the mating sequence have the best chance to win the competition for egg fertilization. This raises the question of the importance of female behavior as determinant of mating order.

Assisted Reproduction Techniques to Improve Reproduction in a Non-Model Species: The Case of the Arabian Bustard (Ardeotis arabs) Conservation Breeding Program.

Artificial reproductive technologies are highly valuable for ex situ conservation. While Arabian bustard populations are declining and extinct in some parts of the range, the International Fund for Houbara Conservation in the United Arab Emirates implemented a conservation breeding program. Since 2012, a total of 1253 eggs were laid through natural reproduction, 1090 were incubated and 379 of these were fertile (fertility rate of 34.8%), leading to the production of 251 chicks. To improve fertility and acquire crucial knowledge for other endangered large birds, artificial reproduction was implemented in 2018 using fresh, refrigerated, and frozen sperm. A total of 720 ejaculates were collected from 12 birds. We analysed these samples for concentration, volume, motility score (0 to 5), viability (eosin/nigrosine), length, and morphology. The first age at collection was 35.7 ± 18.8 months, mean volume was 89.2 ± 65.3 µL, mean concentration was 928 ± 731 sptz/mL and mean motility score was 2.61 ± 0.95. Morphology analyses revealed a bimodal distribution of sperm length. Five hundred and thirty-five ejaculates were cryopreserved and the initial motility score was 3.4 ± 0.7 and 2.0 ± 0.6 after thawing, while the percentage of normal and intact membrane sperm cells decreased from 88.8 ± 7.5% to 52.9 ± 1%. Sixty-five artificial inseminations were performed, leading to a global fertility rate of 84.3%-more precisely, 85.2% and 83.3%, respectively, for fresh and cryopreserved semen. All methods successfully produced fertile eggs, indicating that artificial insemination is an efficient tool for the conservation and genetic management of the species.

Advantages of TRUS-based delineation for high-dose-rate prostate brachytherapy planning.

PURPOSE: To evaluate the variability of prostate contours delineated on computed tomography (CT) and transrectal ultrasound (TRUS). MATERIAL AND METHODS: A TRUS-based high-dose-rate (HDR) brachytherapy procedure was introduced in 2016 in our center. The first thirty patients were additionally imaged with CT immediately after the treatment. In 2018, four different radiation oncologists (ROs: 1, 2, 3, 4) contoured the prostate on both modalities. A volume comparison was performed between CT and TRUS imaging. Using prostate gold fiducial makers, a rigid registration between CT and TRUS was done in 20 of the 30 patients studied. Jaccard index (JI) was computed to evaluate the inter-observer volume delineation agreement. RESULTS: The ratio of TRUS/CT volumes was 0.82 (95% CI: 0.79-0.87%). The mean JI was 87% for CT and 92% for TRUS, when comparing all four ROs; CT and TRUS JIs were significantly different (p < 0.001). The mean JI for the prostate on CT was significantly more consistent (p < 0.001) when comparing RO1, 2, and 3 together (RO1-2, RO1-3, and RO2-3; mean = 89%) than when comparing RO4 (newest to clinical practice) to others (RO1-4, RO2-4, and RO3-4; mean = 85%). For TRUS planning, the mean JI was not significantly different (p > 0.05) when comparing all ROs. CONCLUSIONS: The inter-observer and intra-observer variability were statistically significantly smaller on TRUS compared to CT-based planning, despite varying ROs clinical experiences. The superior soft tissue contrast offered by TRUS obviates the effect of the ROs experience on prostate contour volumes and enables more reproducible prostate delineation.

Enforced monoandry over generations induces a reduction of female investment into reproduction in a promiscuous bird.

While uncovering the costs and benefits of polyandry has attracted considerable attention, assessing the net effect of sexual selection on population fitness requires the experimental manipulation of female mating over generations, which is usually only achievable in laboratory populations of arthropods. However, knowing if sexual selection improves or impairs the expression of life-history traits is key for the management of captive populations of endangered species, which are mostly long-lived birds and mammals. It might therefore be questionable to extrapolate the results gathered on laboratory populations of insects to infer the net effect of sexual selection on populations of endangered species. Here, we used a longitudinal dataset that has been collected on a long-lived bird, the houbara bustard, kept in a conservation breeding program, to investigate the effect of enforced monoandry on female investment into reproduction. In captivity, female houbara bustards are artificially inseminated with sperm collected from a single male (enforced monoandry), or sequentially inseminated with semen of different males (polyandry), allowing postcopulatory sexual selection to operate. We identified female lines that were produced either by monoandrous or polyandrous inseminations over three generations, and we compared reproductive investment of females from the two mating system groups. We found that females in the polyandrous lines had higher investment into reproduction as they laid more eggs per season and produced heavier hatchlings. Higher reproductive investment into reproduction in the polyandrous lines did not result from inherited differences from females initially included in the two mating system groups. These results show that removal of sexual selection can alter reproductive investment after only few generations, potentially hindering population fitness and the success of conservation breeding programs.

PSA outcomes and late toxicity of single-fraction HDR brachytherapy and LDR brachytherapy as monotherapy in localized prostate cancer: A phase 2 randomized pilot study.

PURPOSE: To evaluate the PSA outcomes and the late patient's reported health related quality of life (HRQOL) and toxicity after single-fraction High-Dose-Rate brachytherapy (HDRB) and Low-Dose-Rate brachytherapy (LDRB) for prostate cancer. METHODS: Men with low and favorable intermediate-risk prostate cancer across 3 centres were randomized between monotherapy brachytherapy with either Iodine-125 LDRB or 19 Gy single-fraction HDRB. Biochemical outcomes were evaluated using the Phoenix definition, PSA nadir and absolute PSA value <0.4 ng/mL. Toxicities and HRQOL were recorded at 24 and 36 months. RESULTS: A total of 31 patients were randomized, 15 in the LDRB arm and 16 patients in the HDRB arm. After a median follow-up of 45(36-53) months, 3 patients in the HDRB arm experienced biochemical failure (p = 0.092). Nineteen Gy single-fraction HDRB was associated with significantly higher PSA nadir compared to LDRB (1.02 ± 0.66vs 0.25 ± 0.39, p < 0.0001). Moreover, a significantly larger proportion of patients in the LDRB group had a PSA <0.4 ng/mL (13/15 vs 2/16, p < 0.0001). For late Genito-Urinary, Gastro-Intestinal, and sexual toxicities at 24 and 36 months, no significant differences were found between the 2 arms. As for HRQOL, the IPSS and EPIC-26 urinary irritative score were significantly better for patients treated with HDRB over the first 36 months post-treatment (p = 0.001 and p = 0.01, respectively), reflecting superior HRQOL. CONCLUSION: HDRB resulted in superior HRQOL in the irritative urinary domain compared to LDRB. PSA nadir was significantly lower in the LDRB group and a higher proportion of patients in the LDRB group reached PSA <0.4 ng/mL.

Sensitivity of Oncogenic KRAS-Expressing Cells to CDK9 Inhibition.

Oncogenic forms of KRAS proteins are known to be drivers of pancreatic, colorectal, and lung cancers. The goal of this study is to identify chemical leads that inhibit oncogenic KRAS signaling. We first developed an isogenic panel of mouse embryonic fibroblast (MEF) cell lines that carry wild-type RAS, oncogenic KRAS, and oncogenic BRAF. We validated these cell lines by screening against a tool compound library of 1402 annotated inhibitors in an adenosine triphosphate (ATP)-based cell viability assay. Subsequently, this MEF panel was used to conduct a high-throughput phenotypic screen in a cell viability assay with a proprietary compound library. All 126 compounds that exhibited a selective activity against mutant KRAS were selected and prioritized based on their activities in secondary assays. Finally, five chemical clusters were chosen. They had specific activity against SW620 and LS513 over Colo320 colorectal cancer cell lines. In addition, they had no effects on BRAFV600E, MEK1, extracellular signal-regulated kinase 2 (ERK2), phosphoinositide 3-kinase alpha (PI3Kα), AKT1, or mammalian target of rapamycin (mTOR) as tested in in vitro enzymatic activity assays. Biophysical assays demonstrated that these compounds did not bind directly to KRAS. We further identified the mechanism of action and showed that three of them have CDK9 inhibitory activity. In conclusion, we have developed and validated an isogenic MEF panel that was used successfully to identify RAS oncogenic or wild-type allele-specific vulnerabilities. Furthermore, we identified sensitivity of oncogenic KRAS-expressing cells to CDK9 inhibitors, which warrants future studies of treating KRAS-driven cancers with CDK9 inhibitors.

Paternal age negatively affects sperm production of the progeny.

Parental age has profound consequences for offspring's phenotype. However, whether patrilineal age affects offspring sperm production remains unknown, despite the importance of sperm production for male reproductive success in species facing post-copulatory sexual selection. Using a longitudinal dataset on ejaculate attributes of the houbara bustard, we showed that offspring sired by old fathers had different age-dependent trajectories of sperm production compared to offspring sired by young fathers. Specifically, they produced less sperm (-48%) in their first year of life, and 14% less during their lifetime. Paternal age had the strongest effect, with weak evidence for grandpaternal or great grandpaternal age effects. These results show that paternal age can affect offspring reproductive success by reducing sperm production, establishing an intergenerational link between ageing and sexual selection.

Dose to the bladder neck is not correlated with urinary toxicity in patients with prostate cancer treated with HDR brachytherapy boost.

PURPOSE: The purpose of this study was to evaluate whether the dose to bladder neck (BN) is a predictor of acute and late urinary toxicity after high-dose-rate brachytherapy (HDRB) boost for prostate cancer. METHODS AND MATERIALS: Between 2014 and 2016, patients with prostate cancer treated at our institution with external beam radiation therapy and 15 Gy single-fraction HDRB boost for intermediate- and high-risk disease according to D'Amico definition were reviewed. Intraoperative CT scan-based inverse planning and ultrasound-based inverse planning were performed in 173 and 136 patients, respectively. The following structures were prospectively contoured: prostate, urethra, rectum, bladder, and the BN defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. Dose to the BN was reported only, no constraint was applied. Acute and late urinary toxicity were assessed using the International Prostate Symptom Score (IPSS) and the Common Terminology Criteria for Adverse Events v.4.0. Clinical and dosimetry factors associated with urinary toxicity were analyzed using generalized linear models. RESULTS: A total of 309 patients with median age of 71 years (range 50-89) were included. Median followup was 25 months (range 0-39 months). Using D'Amico definition, 71% of the patients had intermediate-risk disease, whereas 29% had high-risk disease. The mean pretreatment prostate-specific antigen value was 9.65 ng/mL. The mean pretreatment, after 6 weeks and over 6 months IPSSs were 8.34, 12.14, and 10.02, respectively. Urinary obstruction was reported in 14 cases (4.5%). Pretreatment IPSS (p = 0.003) and prostate volume (p = 0.024) were significantly associated with acute and late urinary toxicity. The dose for the most exposed 2 cc (D2cc) of BN was not correlated with acute (p = 0.798) or late urinary toxicity (p = 0.859). BN D2cc was not correlated with urinary obstruction (p = 0.272), but bladder V75 was (p = 0.021). CONCLUSIONS: High pretreatment IPSS, large prostate volume and bladder V75 were the only predictors of acute and late urinary toxicity after HDRB boost in our study. Although BN D2cc was associated with acute and late urinary toxicity after low-dose-rate brachytherapy, no correlation was found after HDRB. A prospective study comparing dose to the BN in HDRB monotherapy would validate the impact of BN dose on acute and late urinary toxicity.

Genetic assessment of a conservation breeding program of the houbara bustard (Chlamydotis undulata undulata) in Morocco, based on pedigree and molecular analyses.

Protection and restoration of species in the wild may require conservation breeding programs under genetic management to minimize deleterious effects of genetic changes that occur in captivity, while preserving populations' genetic diversity and evolutionary resilience. Here, through interannual pedigree analyses, we first assessed the efficiency of a 21-year genetic management, including minimization of mean kinship, inbreeding avoidance, and regular addition of founders, of a conservation breeding program targeting on Houbara bustard (Chlamydotis undulata undulata) in Morocco. Secondly, we compared pedigree analyses, the classical way of assessing and managing genetic diversity in captivity, to molecular analyses based on seven microsatellites. Pedigree-based results indicated an efficient maintenance of the genetic diversity (99% of the initial genetic diversity retained) while molecular-based results indicated an increase in allelic richness and an increase in unbiased expected heterozygosity across time. The pedigree-based average inbreeding coefficient F remained low (between 0.0004 and 0.003 in 2017) while the proportion of highly inbred individuals (F > .1) decreased over time and reached 0.2% in 2017. Furthermore, pedigree-based F and molecular-based individual multilocus heterozygosity were weakly negatively correlated, (Pearson's r = -.061 when considering all genotyped individuals), suggesting that they cannot be considered as alternatives, but rather as complementary sources of information. These findings suggest that a strict genetic monitoring and management, based on both pedigree and molecular tools can help mitigate genetic changes and allow to preserve genetic diversity and evolutionary resilience in conservation breeding programs.

A Phase 2 Randomized Pilot Study Comparing High-Dose-Rate Brachytherapy and Low-Dose-Rate Brachytherapy as Monotherapy in Localized Prostate Cancer.

PURPOSE: To compare health-related quality of life (HRQOL) of high-dose-rate brachytherapy (HDRB) versus low dose-rate brachytherapy (LDRB) for localized prostate cancer in a multi-institutional phase 2 randomized trial. METHODS AND MATERIALS: Men with favorable-risk prostate cancer were randomized between monotherapy brachytherapy with either Iodine-125 LDRB to 144 Gy or single-fraction Iridium-192 HDRB to 19 Gy. HRQOL and urinary toxicity were recorded at baseline and at 1, 3, 6, and 12 months using the Expanded Prostate Cancer Index Composite (EPIC)-26 scoring and the International Prostate Symptom Score (IPSS). Independent samples t test and mixed effects modeling were performed for continuous variables. Time to IPSS resolution, defined as return to its baseline score ±5 points, was calculated using Kaplan-Meier estimator curves with the log-rank test. A multiple-comparison adjusted P value of ≤.05 was considered significant. RESULTS: LDRB and HDRB were performed in 15 and 16 patients, respectively, for a total of 31 patients. At 3 months, patients treated with LDRB had a higher IPSS score (mean, 15.5 vs 6.0, respectively; P = .003) and lower EPIC urinary irritative score (mean, 69.2 vs 85.3, respectively; P = .037) compared with those who received HDRB. On repeated measures at 1, 3, 6, and 12 months, the IPSS (P = .003) and EPIC urinary irritative scores (P = .019) were significantly better in the HDR arm, translating into a lower urinary toxicity profile. There were no significant differences in the EPIC urinary incontinence, sexual, or bowel habit scores between the 2 groups at any measured time point. Time to IPSS resolution was significantly shorter in the HDRB group (mean, 2.0 months) compared with the LDRB group (mean, 6.0 months; P = .028). CONCLUSIONS: HDRB monotherapy is a promising modality associated with a lower urinary toxicity profile and higher HRQOL in the first 12 months compared with LDRB.

Post-copulatory sexual selection allows females to alleviate the fitness costs incurred when mating with senescing males.

Male senescence has detrimental effects on reproductive success and offspring fitness. When females mate with multiple males during the same reproductive bout, post-copulatory sexual selection that operates either through sperm competition or cryptic female choice might allow females to skew fertilization success towards young males and as such limit the fitness costs incurred when eggs are fertilized by senescing males. Here, we experimentally tested this hypothesis. We artificially inseminated female North African houbara bustards with sperm from dyads of males of different (young and old) or similar ages (either young or old). Then, we assessed whether siring success was biased towards young males and we measured several life-history traits of the progeny to evaluate the fitness costs due to advanced paternal age. In agreement with the prediction, we found that siring success was biased towards young males, and offspring sired by old males had impaired hatching success, growth and post-release survival (in females). Overall, our results support the hypothesis that post-copulatory sexual selection might represent an effective mechanism allowing females to avoid the fitness costs of fertilization by senescing partners.

Sperm competition accentuates selection on ejaculate attributes.

Ejaculate attributes are important factors driving the probability of fertilizing eggs. When females mate with several males, competition between sperm to fertilize eggs should accentuate selection on ejaculate attributes. We tested this hypothesis in the North African houbara bustard ( Chlamydotis undulata undulata) by comparing the strength of selection acting on two ejaculate attributes when sperm from single males or sperm from different males were used for insemination. In agreement with the prediction, we found that selection on ejaculate attributes was stronger when sperm of different males competed for egg fertilization. These findings provide the first direct comparison of the strength of selection acting on ejaculate attributes under competitive and non-competitive fertilizations, confirming that sperm competition is a major selective force driving the evolution of ejaculate characteristics.

No evidence for prezygotic postcopulatory avoidance of kin despite high inbreeding depression.

Offspring resulting from mating among close relatives can suffer from impaired fitness through the expression of recessive alleles with deleterious effects. Postcopulatory sperm selection (a prezygotic mechanism of cryptic female choice) has been suggested to be an effective way to avoid inbreeding. To investigate whether postcopulatory female choice allows the avoidance of fertilization by close kin, we performed artificial inseminations in a promiscuous bird, the houbara bustard (Chlamydotis undulata undulata). Females were inseminated with a mix of sperm from triads of males, each constituted of a male genetically unrelated to the female, a first cousin and a half-sibling. When counting the number of eggs sired by unrelated males, cousins or half-siblings, we found a significant deviation from the expected random distribution, with more eggs sired by unrelated males. However, offspring sired by cousins, and especially by half-siblings suffered from high prehatching mortality, suggesting that the observed paternity skew towards unrelated males might reflect differential offspring mortality rather than sperm selection. In agreement with this hypothesis, within-triad siring success was similar for the three parental relatedness categories, but the relationship between siring and hatching success differed across categories. In clutches with high hatching success, unrelated males had the highest success while in clutches with high failure rate, half-siblings had the highest success. Offspring sired by half-siblings also suffered from reduced growth rate during the first three months and higher posthatching mortality. Hence, despite substantial fitness costs associated with fertilization by close relatives, females do not seem to select sperm of unrelated males.

Validation of the Oncentra Brachy Advanced Collapsed cone Engine for a commercial (192)Ir source using heterogeneous geometries.

PURPOSE: To validate the Advanced Collapsed cone Engine (ACE) dose calculation engine of Oncentra Brachy (OcB) treatment planning system using an (192)Ir source. METHODS AND MATERIALS: Two levels of validation were performed, conformant to the model-based dose calculation algorithm commissioning guidelines of American Association of Physicists in Medicine TG-186 report. Level 1 uses all-water phantoms, and the validation is against TG-43 methodology. Level 2 uses real-patient cases, and the validation is against Monte Carlo (MC) simulations. For each case, the ACE and TG-43 calculations were performed in the OcB treatment planning system. ALGEBRA MC system was used to perform MC simulations. RESULTS: In Level 1, the ray effect depends on both accuracy mode and the number of dwell positions. The volume fraction with dose error ≥2% quickly reduces from 23% (13%) for a single dwell to 3% (2%) for eight dwell positions in the standard (high) accuracy mode. In Level 2, the 10% and higher isodose lines were observed overlapping between ACE (both standard and high-resolution modes) and MC. Major clinical indices (V100, V150, V200, D90, D50, and D2cc) were investigated and validated by MC. For example, among the Level 2 cases, the maximum deviation in V100 of ACE from MC is 2.75% but up to ~10% for TG-43. Similarly, the maximum deviation in D90 is 0.14 Gy between ACE and MC but up to 0.24 Gy for TG-43. CONCLUSION: ACE demonstrated good agreement with MC in most clinically relevant regions in the cases tested. Departure from MC is significant for specific situations but limited to low-dose (<10% isodose) regions.

Quantitative Genetics of the Aging of Reproductive Traits in the Houbara Bustard.

Do all traits within an organism age for the same reason? Evolutionary theories of aging share a common assumption: the strength of natural selection declines with age. A corollary is that additive genetic variance should increase with age. However, not all senescent traits display such increases suggesting that other mechanisms may be at play. Using longitudinal data collected from more than 5400 houbara bustards (Chlamydotis undulata) with an exhaustive recorded pedigree, we investigated the genetics of aging in one female reproductive trait (egg production) and three male reproductive traits (courtship display rate, ejaculate size and sperm viability), that display senescence at the phenotypic level. Animal models revealed an increase in additive genetic variance with age for courtship display rate and egg production but an unexpected absence of increased additive genetic variance for ejaculate size and no additive genetic variance for sperm viability. Our results suggest that the mechanisms behind the senescence of some traits are linked with a change in genetic expression, whereas for some other traits, aging may result from the constraints associated with physiological wear and tear on the organism throughout the life of the individual.

The sperm of aging male bustards retards their offspring's development.

Understanding whether the sperm of older males has a diminished capacity to produce successful offspring is a key challenge in evolutionary biology. We investigate this issue using 10 years of reproductive data on captive long-lived houbara bustards (Chlamydotis undulata), where the use of artificial insemination techniques means parents can only influence offspring quality via their gametes. Here we show that paternal aging reduces both the likelihood that eggs hatch and the rate at which chicks grow, with older males producing the lightest offspring after the first month. Surprisingly, this cost of paternal aging on offspring development is of a similar scale to that associated with maternal aging. Fitting with predictions on germline aging, the sperm of immature males produce the fastest growing offspring. Our findings thus indicate that any good genes benefit that might be offered by older 'proven' males will be eroded by aging of their germline DNA.

Does recognized genetic management in supportive breeding prevent genetic changes in life-history traits?

Supportive breeding is one of the last resort conservation strategies to avoid species extinction. Management of captive populations is challenging because several harmful genetic processes need to be avoided. Several recommendations have been proposed to limit these deleterious effects, but empirical assessments of these strategies remain scarce. We investigated the outcome of a genetic management in a supportive breeding for the Houbara Bustard. At the phenotypic level, we found an increase over generations in the mean values of gamete production, body mass and courtship display rate. Using an animal model, we found that phenotypic changes reflected genetic changes as evidenced by an increase in breeding values for all traits. These changes resulted from selection acting on gamete production and to a lesser extent on courtship display. Selection decreased over years for female gametes, emphasizing the effort of managers to increase the contribution of poor breeders to offspring recruited in the captive breeding. Our results shed light on very fast genetic changes in an exemplary captive programme that follows worldwide used recommendations and emphasizes the need of more empirical evidence of the effects of genetic guidelines on the prevention of genetic changes in supportive breeding.