Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study.

BACKGROUND: Circulating tumor DNA (ctDNA) sequencing is a promising approach for tailoring therapy in patients with cancer. We report hereby the results from a prospective study where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors. PATIENTS AND METHODS: Genomic analysis was performed using the FoundationOne Liquid CDx Assay [324 genes, tumor mutational burden (TMB), microsatellite instability status]. Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) tier leading to molecular-based treatment suggestions wherever it was possible. RESULTS: Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 actionable alterations including alteration of the DNA damage repair response pathway (n = 336, 18%), high TMB (>16 mutations/Mb; n = 243, 13%), PIK3CA mutations (n = 150, 8%), ERBB family pathway alterations (n = 127, 7%), PTEN alterations (n = 95, 5%), FGFR alterations (n = 67, 4%) and MET activations (n = 13, 0.7%). The MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (n = 639, 78%), off-label/compassionate use (n = 81, 10%), approved drug (n = 51, 6%), and early access program (n = 48, 6%). In total, 122 patients (21%) were treated. Among the assessable patients (n = 107), 4 (4%) had complete response, 35 (33%) had partial response, 27 (25%) had stable disease, and 41 (38%) a progressive disease as best response. The median progression-free survival and median overall survival were 4.7 months (95% confidence interval 2.7-6.7 months) and 8.3 months (95% confidence interval 4.7-11.9 months) respectively. CONCLUSIONS: ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies.

Mitonuclear interactions modulate nutritional preference.

In nature, organisms are faced with constant nutritional options which fuel key life-history traits. Studies have shown that species can actively make nutritional decisions based on internal and external cues. Metabolism itself is underpinned by complex genomic interactions involving components from both nuclear and mitochondrial genomes. Products from these two genomes must coordinate how nutrients are extracted, used and recycled. Given the complicated nature of metabolism, it is not well understood how nutritional choices are affected by mitonuclear interactions. This is under the rationale that changes in genomic interactions will affect metabolic flux and change physiological requirements. To this end we used a large Drosophila mitonuclear genetic panel, comprising nine isogenic nuclear genomes coupled to nine mitochondrial haplotypes, giving a total of 81 different mitonuclear genotypes. We use a capillary-based feeding assay to screen this panel for dietary preference between carbohydrate and protein. We find significant mitonuclear interactions modulating nutritional choices, with these epistatic interactions also being dependent on sex. Our findings support the notion that complex genomic interactions can place a constraint on metabolic flux. This work gives us deeper insights into how key metabolic interactions can have broad implications on behaviour.

Inheritance through the cytoplasm.

Most heritable information in eukaryotic cells is encoded in the nuclear genome, with inheritance patterns following classic Mendelian segregation. Genomes residing in the cytoplasm, however, prove to be a peculiar exception to this rule. Cytoplasmic genetic elements are generally maternally inherited, although there are several exceptions where these are paternally, biparentally or doubly-uniparentally inherited. In this review, we examine the diversity and peculiarities of cytoplasmically inherited genomes, and the broad evolutionary consequences that non-Mendelian inheritance brings. We first explore the origins of vertical transmission and uniparental inheritance, before detailing the vast diversity of cytoplasmic inheritance systems across Eukaryota. We then describe the evolution of genomic organisation across lineages, how this process has been shaped by interactions with the nuclear genome and population genetics dynamics. Finally, we discuss how both nuclear and cytoplasmic genomes have evolved to co-inhabit the same host cell via one of the longest symbiotic processes, and all the opportunities for intergenomic conflict that arise due to divergence in inheritance patterns. In sum, we cannot understand the evolution of eukaryotes without understanding hereditary symbiosis.

Variation in mitochondrial DNA affects locomotor activity and sleep in Drosophila melanogaster.

Mitochondria are organelles that produce cellular energy in the form of ATP through oxidative phosphorylation, and this primary function is conserved among many taxa. Locomotion is a trait that is highly reliant on metabolic function and expected to be greatly affected by disruptions to mitochondrial performance. To this end, we aimed to examine how activity and sleep vary between Drosophila melanogaster strains with different geographic origins, how these patterns are affected by mitochondrial DNA (mtDNA) variation, and how breaking up co-evolved mito-nuclear gene combinations affect the studied activity traits. Our results demonstrate that Drosophila strains from different locations differ in sleep and activity, and that females are generally more active than males. By comparing activity and sleep of mtDNA variants introgressed onto a common nuclear background in cytoplasmic hybrid (cybrid) strains, we were able to quantify the among-line variance attributable to mitochondrial DNA, and we establish that mtDNA variation affects both activity and sleep, in a sex-specific manner. Altogether our study highlights the important role that mitochondrial genome variation plays on organismal physiology and behaviour.

Assessment of phenotypic diversity within Goliath chickens population in Benin.

Goliath chickens are a new strain of poultry that originated in the department of Zou, commune of Agbangnizoun in the Republic of Benin. The characteristics of this chicken strain have not been well studied. The purpose of this study was to characterize the phenotypic diversity of Goliath chickens in departments of Zou and Couffo. A total of 140 birds made up of 92 females and 48 males were sampled using 18 morphological descriptors. The results showed a wide variation in plumage colour within overall population with the most dominant being black (18.57%), white (17.14%) and red (16.43%). Black (21.74%) and white (20.65%) plumage dominated in females and red in males (35.42%). Coloured beaks and shanks were common in both chicken sexes. Yellow eyes were more common in females (63.04%), while red eyes were the most prevalent in males (43.75%). Comb and wattle colours were red in both sexes. Morphometrically, sexual dimorphism is very marked most of the body measurements with male birds being significantly superior. The average body weight was 3.26 kg in males and 2.78 kg in females. The population was clustered in three morphotypes according to the gradient size. Chickens from Bohicon and Agbangnizoun on the one hand, and those from Zagnanado and Toviklin on the other, formed groups 1 and 2, respectively, while group 3 included individuals from Djidja. 77.96% of observed diversity was due to variation between individuals. Molecular characterization is recommended for a thorough knowledge of the Goliath chicken strain of Benin.

Positive selection on mitochondria may eliminate heritable microbes from arthropod populations.

Diverse eukaryotic taxa carry facultative heritable symbionts, microbes that are passed from mother to offspring. These symbionts are coinherited with mitochondria, and selection favouring either new symbionts, or new symbiont variants, is known to drive loss of mitochondrial diversity as a correlated response. More recently, evidence has accumulated of episodic directional selection on mitochondria, but with currently unknown consequences for symbiont evolution. We therefore employed a population genetic mean field framework to model the impact of selection on mitochondrial DNA (mtDNA) upon symbiont frequency for three generic scenarios of host-symbiont interaction. Our models predict that direct selection on mtDNA can drive symbionts out of the population where a positively selected mtDNA mutation occurs initially in an individual that is uninfected with the symbiont, and the symbiont is initially at low frequency. When, by contrast, the positively selected mtDNA mutation occurs in a symbiont-infected individual, the mutation becomes fixed and in doing so removes symbiont variation from the population. We conclude that the molecular evolution of symbionts and mitochondria, which has previously been viewed from a perspective of selection on symbionts driving the evolution of a neutral mtDNA marker, should be reappraised in the light of positive selection on mtDNA.

Evolving Plastic Responses to External and Genetic Environments.

Phenotypic plasticity can mitigate adaptive trade-offs in fluctuating environments but how plasticity arises is little known. New research documents this process in a bacterial system. We highlight remarkable parallels to the evolution of sexual dimorphism and argue that their approach can aid our understanding of adaptive conflicts between the sexes.

To trigger or not to trigger ovulation in a natural cycle for frozen embryo transfer: a randomized controlled trial.

STUDY QUESTION: Is the clinical pregnancy rate (CPR) following a frozen embryo transfer (FET) in a natural cycle (NC) higher after spontaneous ovulation than after triggered ovulation [natural cycle frozen embryo transfer (NC-FET) versus modified NC-FET]? SUMMARY ANSWER: The CPR did not vary significantly between the two FET preparation protocols. WHAT IS KNOWN ALREADY: Although the use of FET is continuously increasing, the most optimal endometrial preparation protocol is still under debate. For transfer in the NC specifically, conflicting results have been reported in terms of the outcome following spontaneous or triggered ovulation. STUDY DESIGN, SIZE, DURATION: In a tertiary hospital setting, subjects were randomized with a 1:1 allocation into two groups between January 2014 and January 2019. Patients in group A underwent an NC-FET, while in group B, a modified NC-FET was performed with a subcutaneous hCG injection to trigger ovulation. In neither group was additional luteal phase support administered. All embryos were vitrified-warmed on Day 3 and transferred on Day 4 of embryonic development. The primary outcome was CPR at 7 weeks. All patients were followed further until 10 weeks of gestation when the ongoing pregnancy rate (OPR) was defined by the observation of foetal cardiac activity on ultrasound scan. Other secondary outcomes included biochemical pregnancy rate, early pregnancy loss and the number of visits, blood samples and ultrasonographic examinations prior to FET. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 260 patients (130 per study arm) were randomized, of whom 12 withdrew consent after study arm allocation. A total of 3 women conceived spontaneously before initiating the study cycle and 16 did not start for personal or medical reasons. Of the 229 actually commencing monitoring for the study FET cycle, 7 patients needed to be switched to a hormonal replacement treatment protocol due to the absence of follicular development, 12 had no embryo available for transfer after warming and 37 had a spontaneous LH surge before the ovulation trigger could be administered, although they were allocated to group B. Given the above, an intention-to-treat (ITT) analysis was performed taking into account 248 patients (125 in group A and 123 in group B), as well as a per protocol (PP) analysis on a subset of 173 patients (110 in group A and 63 in group B). MAIN RESULTS AND THE ROLE OF CHANCE: Demographic features were evenly distributed between the study groups, as were the relevant fresh and frozen ET cycle characteristics. According to the ITT analysis, the CPR and OPR in group A (33.6% and 27.2%, respectively) and group B (29.3% and 24.4%, respectively) did not vary significantly [relative risk (RR) 0.87, 95% CI (0.60;1.26), P = 0.46 and RR 0.90, 95% CI (0.59;1.37), P = 0.61, respectively]. Biochemical pregnancy rate and early pregnancy loss were also found to be not statistically significantly different between the groups. In contrast, more clinic visits and blood samplings for cycle monitoring were required in the NC-FET group (4.05 ± 1.39) compared with the modified NC-FET group (3.03 ± 1.16, P = <0.001), while the number of ultrasound scans performed were comparable (1.70 ± 0.88 in group A versus 1.62 ± 1.04 in group B). The additional PP analysis was in line with the ITT results: CPR in group A was 36.4% versus 38.1% in group B [RR 1.05, 95% CI (0.70;1.56), P = 0.82]. LIMITATIONS, REASONS FOR CAUTION: The results are limited by the high drop-out rate for the PP analysis in the modified NC-FET group as more than one-third of the subjects allocated to this group ovulated spontaneously before ovulation triggering. Nonetheless, this issue is inherent to routine clinical practice and is an important observation of an event that can only be avoided by performing a very extensive monitoring that limits the practical advantages associated with modified NC-FET. Furthermore, although this is the largest randomized controlled trial (RCT) investigating this specific research question so far, a higher sample size would allow smaller differences in clinical outcome to be detected, since currently they may be left undetected. WIDER IMPLICATIONS OF THE FINDINGS: This RCT adds new high-quality evidence to the existing controversial literature concerning the performance of NC-FET versus modified NC-FET. Based on our results showing no statistically significant differences in clinical outcomes between the protocols, the treatment choice may be made according to the patient's and treating physician's preferences. However, the modified NC-FET strategy reduces the need for hormonal monitoring and may therefore be considered a more patient-friendly and potentially cost-effective approach. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was available for this study. None of the authors have a conflict of interest to declare with regard to this study. TRIAL REGISTRATION NUMBER: NCT02145819. TRIAL REGISTRATION DATE: 8 January 2014. DATE OF FIRST PATIENT'S ENROLMENT: 21 January 2014.

Nutritional geometry of mitochondrial genetic effects on male fertility.

Organismal fitness is partly determined by how well the nutritional intake matches sex-specific metabolic requirements. Metabolism itself is underpinned by complex genomic interactions involving products from both nuclear and mitochondrial genomes. Products from these two genomes must coordinate how nutrients are extracted, used and recycled, processes vital for fuelling reproduction. Given the complicated nature of metabolism, it is not well understood how the functioning of these two genomes is modulated by nutrients. Here we use nutritional geometry techniques on Drosophila lines that only differ in their mtDNA, with the aim to understand if there is nutrient-dependent mitochondrial genetic variance for male reproduction. We first find genetic variance for diet consumption, indicating that flies are consuming different amounts of food to meet new physiological requirements. We then find an interaction between mtDNA and diet for fitness, suggesting that the mtDNA plays a role in modulating diet-dependent fitness. Our results enhance our basic understanding of nutritional health and our chimeric genomes.

Meiotic drive reduces egg-to-adult viability in stalk-eyed flies.

A number of species are affected by Sex-Ratio (SR) meiotic drive, a selfish genetic element located on the X-chromosome that causes dysfunction of Y-bearing sperm. SR is transmitted to up to 100% of offspring, causing extreme sex ratio bias. SR in several species is found in a stable polymorphism at a moderate frequency, suggesting there must be strong frequency-dependent selection resisting its spread. We investigate the effect of SR on female and male egg-to-adult viability in the Malaysian stalk-eyed fly, Teleopsis dalmanni. SR meiotic drive in this species is old, and appears to be broadly stable at a moderate (approx. 20%) frequency. We use large-scale controlled crosses to estimate the strength of selection acting against SR in female and male carriers. We find that SR reduces the egg-to-adult viability of both sexes. In females, homozygous females experience greater reduction in viability (sf = 0.242) and the deleterious effects of SR are additive (h = 0.511). The male deficit in viability (sm = 0.214) is not different from that in homozygous females. The evidence does not support the expectation that deleterious side effects of SR are recessive or sex-limited. We discuss how these reductions in egg-to-adult survival, as well as other forms of selection acting on SR, may maintain the SR polymorphism in this species.

Preoperative evaluation of small bowel complications in Crohn's disease: comparison of diffusion-weighted and contrast-enhanced MR imaging.

PURPOSE: To compare the accuracy of MR enterography (MRE) using combined T2-weighted and contrast-enhanced (CE) sequences with that of combined T2- and diffusion-weighted (DW) sequences for the detection of complex enteric Crohn's disease (CD). MATERIALS: Thirty-eight patients who underwent surgery for CD complications and preoperative MRE from 2011 to 2016 were included. MRE examinations were blindly analyzed independently by one junior and one senior abdominal radiologist for the presence of fistula, stenosis and abscesses. During a first reading session, T2-weighted images (WI), steady-state sequences and DW-MRE were reviewed (set 1). During a separate distant session, T2-WI, True-FISP and CE-MRE were reviewed (set 2). Performance of each reader was evaluated by comparison with the standard of reference established using intraoperative and pathological findings. RESULTS: Forty-eight fistulas, 43 stenoses and 11 abscesses were found. For the senior radiologist, sensitivity for the detection of fistula, stenosis and abscess ranged from 80% to 100% for set 1 and 88% to 100% for set 2 and specificity ranged from 56% to 70% for set 1 and 53% to 93% for set 2, with no significant difference between the sets (p = 0.342-0.429). For the junior radiologist, sensitivity ranged from 53% to 63% for set 1 and 64% to 88% for set 2 and specificity ranged from 0% to 25% for set 1 and 17% to 40% for set 2 (p = 0.001 and 0.007, respectively). CONCLUSION: For a senior radiologist, DW-MRE has similar sensitivity as CE-MRE for the detection of CD complications. For a junior radiologist, CE-MRE yields the best results compared with DW-MRE. KEY POINTS: • For experienced readers, DWI has similar diagnostic capability as contrast-enhanced MR imaging for the diagnosis of Crohn's disease complications. • For senior radiologists, gadolinium chelate injection could be waived for the diagnosis of Crohn's disease complications. • The interpretation of DWI for Crohn's disease complications requires some experience.

Experimental Support That Natural Selection Has Shaped the Latitudinal Distribution of Mitochondrial Haplotypes in Australian Drosophila melanogaster.

Cellular metabolism is regulated by enzyme complexes within the mitochondrion, the function of which are sensitive to the prevailing temperature. Such thermal sensitivity, coupled with the observation that population frequencies of mitochondrial haplotypes tend to associate with latitude, altitude, or climatic regions across species distributions, led to the hypothesis that thermal selection has played a role in shaping standing variation in the mitochondrial DNA (mtDNA) sequence. This hypothesis, however, remains controversial, and requires evidence that the distribution of haplotypes observed in nature corresponds with the capacity of these haplotypes to confer differences in thermal tolerance. Specifically, haplotypes predominating in tropical climates are predicted to encode increased tolerance to heat stress, but decreased tolerance to cold stress. We present direct evidence for these predictions, using mtDNA haplotypes sampled from the Australian distribution of Drosophila melanogaster. We show that the ability of flies to tolerate extreme thermal challenges is affected by sequence variation across mtDNA haplotypes, and that the thermal performance associated with each haplotype corresponds with its latitudinal prevalence. The haplotype that predominates at low (subtropical) latitudes confers greater resilience to heat stress, but lower resilience to cold stress, than haplotypes predominating at higher (temperate) latitudes. We explore molecular mechanisms that might underlie these responses, presenting evidence that the effects are in part regulated by SNPs that do not change the protein sequence. Our findings suggest that standing variation in the mitochondrial genome can be shaped by thermal selection, and could therefore contribute to evolutionary adaptation under climatic stress.

Mitochondrial genetic effects on reproductive success: signatures of positive intrasexual, but negative intersexual pleiotropy.

Theory predicts that maternal inheritance of mitochondria will facilitate the accumulation of mtDNA mutations that are male biased, or even sexually antagonistic, in effect. While there are many reported cases of mtDNA mutations conferring cytoplasmic male sterility in plants, historically it was assumed such mutations would not persist in the streamlined mitochondrial genomes of bilaterian metazoans. Intriguingly, recent cases of mitochondrial variants exerting male biases in effect have come to light in bilaterians. These cases aside, it remains unknown whether the mitochondrial genetic variation affecting phenotypic expression, and in particular reproductive performance, in bilaterians is routinely composed of sex-biased or sex-specific variation. If selection consistently favours mtDNA variants that augment female fitness, but at cost to males, this could shape patterns of pleiotropy and lead to negative intersexual correlations across mtDNA haplotypes. Here, we show that genetic variation across naturally occurring mitochondrial haplotypes affects components of reproductive success in both sexes, in the fruit fly Drosophila melanogaster We find that intrasexual correlations across mitochondrial haplotypes, for components of reproductive success, are generally positive, while intersexual correlations are negative. These results accord with theoretical predictions, suggesting that maternal inheritance has led to the fixation of numerous mutations of sexually antagonistic effect.

Coadaptation of mitochondrial and nuclear genes, and the cost of mother's curse.

Strict maternal inheritance renders the mitochondrial genome susceptible to accumulating mutations that harm males, but are otherwise benign or beneficial for females. This 'mother's curse' effect can degrade male survival and fertility if unopposed by counteracting evolutionary processes. Coadaptation between nuclear and mitochondrial genomes-with nuclear genes evolving to compensate for male-harming mitochondrial substitutions-may ultimately resolve mother's curse. However, males are still expected to incur a transient fitness cost during mito-nuclear coevolution, and it remains unclear how severe such costs should be. We present a population genetic analysis of mito-nuclear coadaptation to resolve mother's curse effects, and show that the magnitude of the 'male mitochondrial load'-the negative impact of mitochondrial substitutions on male fitness components-may be large, even when genetic variation for compensatory evolution is abundant. We also find that the male load is surprisingly sensitive to population size: male fitness costs of mito-nuclear coevolution are particularly pronounced in both small and large populations, and minimized in populations of intermediate size. Our results reveal complex interactions between demography and genetic constraints during the resolution of mother's curse, suggesting potentially widespread species differences in susceptibility to mother's curse effects.

Impact of late-follicular phase elevated serum progesterone on cumulative live birth rates: is there a deleterious effect on embryo quality?

STUDY QUESTION: Is elevated late-follicular phase progesterone (EP) associated with a deleterious impact on embryo quality (EQ) and cumulative live birth rates (LBRs)? SUMMARY ANSWER: EP was associated with a decrease in embryo utilization and cumulative LBRs. WHAT IS KNOWN ALREADY: Ovarian stimulation promotes the production of progesterone (P) which adversely affects IVF pregnancy outcomes. However, evidence regarding a potential association between EP an EQ is lacking. STUDY DESIGN, SIZE, DURATION: A retrospective analysis of all GnRH antagonist down-regulated ICSI cycles followed by a fresh embryo transfer (ET) between 2010 and 2015 was performed. The sample was stratified according to the following P levels on the day of ovulation triggering: ≤0.50, 0.51-1.49 and ≥1.50 ng/ml. The primary outcomes were embryo utilization rates (number of embryos transferred or cryopreserved) and cumulative LBR, defined as the occurrence of the first live-birth after either the fresh or one of the subsequent frozen ET. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 3400 cycles were included in the analysis, using multivariable regression to account for potential confounding. MAIN RESULTS AND THE ROLE OF CHANCE: Female age and the number of oocytes retrieved increased significantly with increasing serum P values. Utilization rates decreased linearly as P increased for Day 3 embryos (72.3, 63.0 and 45.4%, respectively), while for Day 5 embryos only the EP group was associated with a significant decrease (48.8, 47.8 and 38.8%, respectively). EP was also associated with decreased fresh and cumulative LBRs. LIMITATIONS REASONS FOR CAUTION: The main limitations of this study were its retrospective nature and the fact that it was restricted to GnRH antagonist cycles. WIDER IMPLICATIONS OF THE FINDINGS: These results raise the question whether EP may also be associated with a decrease in cumulative pregnancy outcomes by increasing embryo wastage. Further studies may evaluate the potential benefit of additional measures besides the freeze-all strategy to avoid this issue, such as lowering the stimulation dose or applying a step-down protocol. STUDY FUNDING/COMPETING INTEREST(S): None.

Prenatal prediction of postnatal large-for-dates neonates using a simplified MRI method: comparison with conventional 2D ultrasound estimates.

OBJECTIVE: To evaluate the performance of a simple semi-automated method for estimation of fetal weight (EFW) using magnetic resonance imaging (MRI) as compared with two-dimensional (2D) ultrasound (US) for the prediction of large-for-dates neonates. METHODS: Data of two groups of women with singleton pregnancy between March 2011 and May 2016 were retrieved from our database and evaluated retrospectively: the first group included women who underwent US-EFW and MRI-EFW within 48 h before delivery and the second group included women who had these evaluations between 35 + 0 weeks and 37 + 6 weeks of gestation, more than 48 h before delivery. US-EFW was based on Hadlock et al. and MRI-EFW on the formula described by Baker et al. For MRI-EFW, planimetric measurement of the fetal body volume (FBV) was performed using a semi-automated method and the time required for measurement was noted. Outcome measure was the performance of MRI-EFW vs US-EFW in the prediction of large-for-dates neonates, both ≤ 48 h and > 48 h before delivery. Receiver-operating characteristics (ROC) curves for each method were compared using the DeLong method. RESULTS: Of the 270 women included in the first group, 48 (17.8%) newborns had birth weight ≥ 90th centile and 30 (11.1%) ≥ 95th centile. The second group included 83 women, and nine (10.8%) newborns had birth weight ≥ 95th centile. Median time needed for FBV planimetric measurements in all 353 fetuses was 3.5 (range, 1.5-5.5) min. The area under the ROC curve (AUC) for prediction of large-for-dates neonates by prenatal MRI performed within 48 h before delivery was significantly higher than that by US (for birth weight ≥ 90th centile, difference between AUCs = 0.085, standard error (SE) = 0.020, P < 0.001; for birth weight ≥ 95th centile, difference between AUCs = 0.036, SE = 0.014, P = 0.01). Similarly, MRI-EFW was better than US-EFW in predicting birth weight ≥ 95th centile when both examinations were performed > 48 h prior to delivery (difference between AUCs = 0.077, SE = 0.039, P = 0.045). CONCLUSION: MRI planimetry using our purpose-designed semi-automated method is not time-consuming. The predictive performance of MRI-EFW performed immediately prior to or remote from delivery is significantly better than that of US-EFW for the prediction of large-for-dates neonates. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

A prospective examination of circulating tumor cell profiles in non-small-cell lung cancer molecular subgroups.

BACKGROUND: We report the first study examining the clinical, numerical and biological properties of circulating tumor cells according to molecular subtypes of non-small-cell lung cancer. PATIENTS AND METHODS: 125 patients with treatment-naïve stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype, and survival were assessed. RESULTS: 51/125 patients (40.8%) were total CTC+ and 26/125 (20.8%) were vim CTC+ at baseline. Multivariate analysis showed patients with ≥5 total CTCs had significantly reduced OS (HR 0.55, 95% CI 0.33-0.92, P = 0.022) but not PFS (HR 0.68, 95% CI 0.42-1.1, P = 0.118) compared to patients with <5 total CTCs. No OS difference was evident between vim+ CTC and vim-negative CTC patients overall (HR 1.24, 95% CI 0.67-2.28, P = 0.494), but after subdivision according to NSCLC driver mutation, we found an increase of vim+ CTCs in the EGFR-mutated subgroup (N = 21/94 patients; mean 1.24 vs 1.22 vim+ CTCs, P = 0.013), a reduction of total CTCs in the ALK-rearranged subgroup (N = 13/90 patients; mean 1.69 vs 5.82 total CTCs, P = 0.029), and a total absence of vim+ CTCs in KRAS-mutated adenocarcinomas (N = 19/78 patients; mean 0 vs 1.4 vim+ CTCs, P = 0.006). CONCLUSIONS: We validate that the baseline presence of ≥5 total CTCs in advanced NSCLC confers a poor prognosis. CTCs from EGFR-mutant NSCLC express epithelial-mesenchymal transition characteristics, not seen in CTCs from patients with KRAS-mutant adenocarcinoma.

Sex and genotype effects on nutrient-dependent fitness landscapes in Drosophila melanogaster.

The sexes perform different reproductive roles and have evolved sometimes strikingly different phenotypes. One focal point of adaptive divergence occurs in the context of diet and metabolism, and males and females of a range of species have been shown to require different nutrients to maximize their fitness. Biochemical analyses in Drosophila melanogaster have confirmed that dimorphism in dietary requirements is associated with molecular sex differences in metabolite titres. In addition, they also showed significant within-sex genetic variation in the metabolome. To date however, it is unknown whether this metabolic variation translates into differences in reproductive fitness. The answer to this question is crucial to establish whether genetic variation is selectively neutral or indicative of constraints on sex-specific physiological adaptation and optimization. Here we assay genetic variation in consumption and metabolic fitness effects by screening male and female fitness of thirty D. melanogaster genotypes across four protein-to-carbohydrate ratios. In addition to confirming sexual dimorphism in consumption and fitness, we find significant genetic variation in male and female dietary requirements. Importantly, these differences are not explained by feeding responses and probably reflect metabolic variation that, in turn, suggests the presence of genetic constraints on metabolic dimorphism.

Novel hemotropic mycoplasmas are widespread and genetically diverse in vampire bats.

Bats (Order: Chiroptera) have been widely studied as reservoir hosts for viruses of concern for human and animal health. However, whether bats are equally competent hosts of non-viral pathogens such as bacteria remains an important open question. Here, we surveyed blood and saliva samples of vampire bats from Peru and Belize for hemotropic Mycoplasma spp. (hemoplasmas), bacteria that can cause inapparent infection or anemia in hosts. 16S rRNA gene amplification of blood showed 67% (150/223) of common vampire bats (Desmodus rotundus) were infected by hemoplasmas. Sequencing of the 16S rRNA gene amplicons revealed three novel genotypes that were phylogenetically related but not identical to hemoplasmas described from other (non-vampire) bat species, rodents, humans, and non-human primates. Hemoplasma prevalence in vampire bats was highest in non-reproductive and young individuals, did not differ by country, and was relatively stable over time (i.e., endemic). Metagenomics from pooled D. rotundus saliva from Peru detected non-hemotropic Mycoplasma species and hemoplasma genotypes phylogenetically similar to those identified in blood, providing indirect evidence for potential direct transmission of hemoplasmas through biting or social contacts. This study demonstrates vampire bats host several novel hemoplasmas and sheds light on risk factors for infection and basic transmission routes. Given the high frequency of direct contacts that arise when vampire bats feed on humans, domestic animals, and wildlife, the potential of these bacteria to be transmitted between species should be investigated in future work.