Artificial selection reveals the energetic expense of producing larger eggs

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: The amount of resources provided by the mother before birth has important and long-lasting effects on offspring fitness. Despite this, there is a large amount of variation in maternal investment seen in natural populations. Life-history theory predicts that this variation is maintained through a trade-off between the benefits of high maternal investment for the offspring and the costs of high investment for the mother. However, the proximate mechanisms underlying these costs of reproduction are not well understood. Here we used artificial selection for high and low maternal egg investment in a precocial bird, the Japanese quail (Coturnix japonica) to quantify costs of maternal reproductive investment. RESULTS: We show that females from the high maternal investment lines had significantly larger reproductive organs, which explained their overall larger body mass, and resulted in a higher resting metabolic rate (RMR). Contrary to our expectations, this increase in metabolic activity did not lead to a higher level of oxidative damage. CONCLUSIONS: This study is the first to provide experimental evidence for metabolic costs of increased per offspring investment.The study was financially supported by the Swiss National Science Foundation (PP00P3 128386 and 458 PP00P3 157455 to BT)

High Energy Bounds on Soft N=4 SYM Amplitudes from AdS/CFT

Using the AdS/CFT correspondence, we study the high-energy behavior of colorless dipole elastic scattering amplitudes in N=4 SYM gauge theory through the Wilson loop correlator formalism and Euclidean to Minkowskian analytic continuation. The purely elastic behavior obtained at large impact-parameter L, through duality from disconnected AdS_5 minimal surfaces beyond the Gross-Ooguri transition point, is combined with unitarity and analyticity constraints in the central region. In this way we obtain an absolute bound on the high-energy behavior of the forward scattering amplitude due to the graviton interaction between minimal surfaces in the bulk. The dominant "Pomeron" intercept is bounded by alpha less than or equal to 11/7 using the AdS/CFT constraint of a weak gravitational field in the bulk. Assuming the elastic eikonal approximation in a larger impact-parameter range gives alpha between 4/3 and 11/7. The actual intercept becomes 4/3 if one assumes the elastic eikonal approximation within its maximally allowed range L larger than exp{Y/3}, where Y is the total rapidity. Subleading AdS/CFT contributions at large impact-parameter due to the other d=10 supergravity fields are obtained. A divergence in the real part of the tachyonic KK scalar is cured by analyticity but signals the need for a theoretical completion of the AdS/CFT scheme.Comment: 25 pages, 3 eps figure

Reggeon exchange from gauge/gravity duality

We perform the analysis of quark-antiquark Reggeon exchange in meson-meson scattering, in the framework of the gauge/gravity correspondence in a confining background. On the gauge theory side, Reggeon exchange is described as quark-antiquark exchange in the t channel between fast projectiles. The corresponding amplitude is represented in terms of Wilson loops running along the trajectories of the constituent quarks and antiquarks. The paths of the exchanged fermions are integrated over, while the "spectator" fermions are dealt with in an eikonal approximation. On the gravity side, we follow a previously proposed approach, and we evaluate the Wilson-loop expectation value by making use of gauge/gravity duality for a generic confining gauge theory. The amplitude is obtained in a saddle-point approximation through the determination near the confining horizon of a Euclidean "minimal surface with floating boundaries", i.e., by fixing the trajectories of the exchanged quark and antiquark by means of a minimisation procedure, which involves both area and length terms. After discussing, as a warm-up exercise, a simpler problem on a plane involving a soap film with floating boundaries, we solve the variational problem relevant to Reggeon exchange, in which the basic geometry is that of a helicoid. A compact expression for the Reggeon-exchange amplitude, including the effects of a small fermion mass, is then obtained through analytic continuation from Euclidean to Minkowski space-time. We find in particular a linear Regge trajectory, corresponding to a Regge-pole singularity supplemented by a logarithmic cut induced by the non-zero quark mass. The analytic continuation leads also to companion contributions, corresponding to the convolution of the same Reggeon-exchange amplitude with multiple elastic rescattering interactions between the colliding mesons.Comment: 60+1 pages, 14 figure

Cost-utility model of brivaracetam in the adjunctive treatment of patients with epilepsy in Spain

[EN] Objective This study aims to assess the cost utility of Brivaracetam compared with the third-generation anti-epileptic drugs used as standard care. Methods A cost utility analysis of Brivaracetam was carried out with other third-generation comparators. The treatment pathway of a hypothetical cohort over a period of 2 years was simulated using the Markov model. Data for effectiveness and the QALYs of each health status for epilepsy, as well as for the disutilities of adverse events of treatments, were analyzed through a studies review. The cost of the anti-epileptics and the use of medical resources linked to the different health statuses were taken into consideration. A probabilistic sensitivity analysis was performed using a Monte Carlo simulation. Results Brivaracetam was shown to be the dominant alternative, with Incremental Cost Utility Ratio (ICUR) values from -11,318 for Lacosamide to -128,482 for Zonisamide. The probabilistic sensitivity analysis validates these results. The ICUR sensitivity is greater for increases in the price of Brivaracetam than for decreases, and for Eslicarbizapine over the other adjunctives considered in the analysis. Conclusions Treatment with Brivaracetam resulted in cost effective and incremental quality adjusted life years come at an acceptable cost.Barrachina Martínez, I.; Vivas-Consuelo, D.; Reyes-Santias, F. (2020). Cost-utility model of brivaracetam in the adjunctive treatment of patients with epilepsy in Spain. Expert review of pharmacoeconomics & outcomes research (Online). 1-10. https://doi.org/10.1080/14737167.2021.1838899S110WHO | Epilepsy: aISBN public health imperative. ISBN 978-92-4-151593-1. World Health Organization. 2019. Printed in Thailand.Ngugi, A. K., Kariuki, S. M., Bottomley, C., Kleinschmidt, I., Sander, J. W., & Newton, C. R. (2011). Incidence of epilepsy: A systematic review and meta-analysis. Neurology, 77(10), 1005-1012. doi:10.1212/wnl.0b013e31822cfc90Henning, O., Landmark, C. J., Henning, D., Nakken, K. O., & Lossius, M. I. (2019). Challenges in epilepsy—The perspective of Norwegian epilepsy patients. Acta Neurologica Scandinavica, 140(1), 40-47. doi:10.1111/ane.13098Brodie, M. J. (2005). Diagnosing and predicting refractory epilepsy. Acta Neurologica Scandinavica, 112(s181), 36-39. doi:10.1111/j.1600-0404.2005.00507.xGarcía-Ramos, R., Pastor, A. G., Masjuan, J., Sánchez, C., & Gil, A. (2011). FEEN: Informe sociosantario FEEN sobre la epilepsia en España. Neurología, 26(9), 548-555. doi:10.1016/j.nrl.2011.04.002Kwan, P., & Brodie, M. J. (2000). Early Identification of Refractory Epilepsy. New England Journal of Medicine, 342(5), 314-319. doi:10.1056/nejm200002033420503Brodie, M. J. (2008). Epilepsy: randomised trials and genetic tribulations. The Lancet Neurology, 7(1), 7-8. doi:10.1016/s1474-4422(07)70301-0French, J. A. (2006). Refractory Epilepsy: One Size Does Not Fit All. Epilepsy Currents, 6(6), 177-180. doi:10.1111/j.1535-7511.2006.00137.xLaxer, K. D., Trinka, E., Hirsch, L. J., Cendes, F., Langfitt, J., Delanty, N., … Benbadis, S. R. (2014). The consequences of refractory epilepsy and its treatment. Epilepsy & Behavior, 37, 59-70. doi:10.1016/j.yebeh.2014.05.031Giordano, C., Marchiò, M., Timofeeva, E., & Biagini, G. (2014). Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets. Frontiers in Neurology, 5. doi:10.3389/fneur.2014.00063European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Briviact brivaracetam. Assessment Report EMA/CHMP/822086/2015 Nov.Markham, A. (2016). Brivaracetam: First Global Approval. Drugs, 76(4), 517-522. doi:10.1007/s40265-016-0555-6Willems, L. M., Bauer, S., Rosenow, F., & Strzelczyk, A. (2019). Recent advances in the pharmacotherapy of epilepsy: brivaracetam and perampanel as broad-spectrum antiseizure drugs for the treatment of epilepsies and status epilepticus. Expert Opinion on Pharmacotherapy, 20(14), 1755-1765. doi:10.1080/14656566.2019.1637420Craig, D., Rice, S., Paton, F., Fox, D., & Woolacott, N. (2013). Retigabine for the Adjunctive Treatment of Adults with Partial-Onset Seizures in Epilepsy with and without Secondary Generalization. PharmacoEconomics, 31(2), 101-110. doi:10.1007/s40273-012-0018-1Charokopou, M., Harvey, R., Srivastava, K., Brandt, C., & Borghs, S. (2019). Relative performance of brivaracetam as adjunctive treatment of focal seizures in adults: a network meta-analysis. Current Medical Research and Opinion, 35(8), 1345-1354. doi:10.1080/03007995.2019.1584501Chhatwal J. Changing cycle lengths in state-transition models: doing it the right way; [cited 2018 Jan 23]. Available from: https://www.ispor.org/News/Connections_methodology_state-transition-models.PDFMulhern, B., Rowen, D., Snape, D., Jacoby, A., Marson, T., Hughes, D., … Brazier, J. (2014). Valuations of epilepsy-specific health states: a comparison of patients with epilepsy and the general population. Epilepsy & Behavior, 36, 12-17. doi:10.1016/j.yebeh.2014.04.011Kristian, B., Wachtmeister, K., Stefan, F., & Forsgren, L. (2013). Retigabine as add-on treatment of refractory epilepsy - a cost-utility study in a Swedish setting. Acta Neurologica Scandinavica, 127(6), 419-426. doi:10.1111/ane.12077Vera-Llonch, M., Brandenburg, N. A., & Oster, G. (2008). Cost-effectiveness of Add-on Therapy with Pregabalin in Patients with Refractory Partial Epilepsy. Epilepsia, 49(3), 431-437. doi:10.1111/j.1528-1167.2007.01279.xSimoens, S. (2010). Pharmacoeconomics of anti-epileptic drugs as adjunctive therapy for refractory epilepsy. Expert Review of Pharmacoeconomics & Outcomes Research, 10(3), 309-315. doi:10.1586/erp.10.18Wijnen, B. F. M., van Mastrigt, G. A. P. G., Evers, S. M. A. A., Gershuni, O., Lambrechts, D. A. J. E., Majoie, M. H. J. M., … de Kinderen, R. J. A. (2017). A systematic review of economic evaluations of treatments for patients with epilepsy. Epilepsia, 58(5), 706-726. doi:10.1111/epi.13655Boeck, J. D., Verpoorten, K., Luyten, K., & Coninx, K. (2007). A Comparison between Decision Trees and Markov Models to Support Proactive Interfaces. 18th International Conference on Database and Expert Systems Applications (DEXA 2007). doi:10.1109/dexa.2007.94Zhang, Y., Wu, H., Denton, B. T., Wilson, J. R., & Lobo, J. M. (2017). Probabilistic sensitivity analysis on Markov models with uncertain transition probabilities: an application in evaluating treatment decisions for type 2 diabetes. Health Care Management Science, 22(1), 34-52. doi:10.1007/s10729-017-9420-8Swallow, E., Fang, A., Signorovitch, J., Plumb, J., & Borghs, S. (2017). Can Matching-Adjusted Indirect Comparison Methods Mitigate Placebo Response Differences Among Patient Populations in Adjunctive Trials of Brivaracetam and Levetiracetam? CNS Drugs, 31(10), 899-910. doi:10.1007/s40263-017-0462-8Malyshkina NV, Mannering FL. Markov switching multinomial logit model: an application to accident injury severities; 2008 [cited 2019 Sep 25]. Available from: http://arxiv.org/abs/0811.3644Hawkins, N., Epstein, D., Drummond, M., Wilby, J., Kainth, A., Chadwick, D., & Sculpher, M. (2005). Assessing the Cost-Effectiveness of New Pharmaceuticals in Epilepsy in Adults: The Results of a Probabilistic Decision Model. Medical Decision Making, 25(5), 493-510. doi:10.1177/0272989x05280559Agencia Española del Medicamento. Utilización de medicamentos antiepilépticos en España durante el periodo 2008–2016 [Internet]; 2017 [cited 2019 Sep 25]. Available from: https://www.aemps.gob.es/medicamentosUsoHumano/observatorio/docs/antiepilepticos-periodo-2008-2016.pdfMegiddo, I., Colson, A., Chisholm, D., Dua, T., Nandi, A., & Laxminarayan, R. (2016). Health and economic benefits of public financing of epilepsy treatment in India: An agent‐based simulation model. Epilepsia, 57(3), 464-474. doi:10.1111/epi.13294De Andrés-Nogales, F., Oyagüez, I., Álvarez-Sala, L. A., García-Bragado, F., Navarro, A., González, P., … Soto, J. (2017). Análisis coste-efectividad y coste-utilidad de apixaban frente a dabigatrán y rivaroxaban en el tratamiento y prevención secundaria del tromboembolismo venoso. PharmacoEconomics Spanish Research Articles, 14(1), 7-18. doi:10.1007/s40277-016-0064-8Fricke-Galindo, I., Jung-Cook, H., LLerena, A., & López-López, M. (2018). Farmacogenética de reacciones adversas a fármacos antiepilépticos. Neurología, 33(3), 165-176. doi:10.1016/j.nrl.2015.03.005Steinhoff, B. J., Bacher, M., Bucurenciu, I., Hillenbrand, B., Intravooth, T., Kornmeier, R., … Staack, A. M. (2017). Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy—A monocenter survey. Seizure, 48, 11-14. doi:10.1016/j.seizure.2017.03.010De Kinderen, R. J. A., Wijnen, B. F. M., van Breukelen, G., Postulart, D., Majoie, M. H. J. M., Aldenkamp, A. P., & Evers, S. M. A. A. (2016). From clinically relevant outcome measures to quality of life in epilepsy: A time trade-off study. Epilepsy Research, 125, 24-31. doi:10.1016/j.eplepsyres.2016.05.005Cortés, J.-C., Navarro-Quiles, A., Romero, J.-V., & Roselló, M.-D. (2017). Randomizing the parameters of a Markov chain to model the stroke disease: A technical generalization of established computational methodologies towards improving real applications. Journal of Computational and Applied Mathematics, 324, 225-240. doi:10.1016/j.cam.2017.04.04

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE Study): prospective cohort study and systematic review

OBJECTIVES: To determine the yield of antenatal exome sequencing (ES) over chromosome microarray (CMA) / conventional karyotyping in; (i) any prenatally diagnosed congenital heart disease (CHD); (ii) isolated CHD; (iii) multi‐system CHD and; (iv) CHD by phenotypic subgroup. / METHODS: A prospective cohort study of 197 trios undergoing ES following CMA/karyotype because CHD was identified prenatally and a systematic review of the literature was performed. MEDLINE, EMBASE and CINAHL (2000–Oct 2019) databases were searched electronically. Selected studies included those with; (i) >3 cases; (ii) initiation of testing based upon a prenatal phenotype only and; (iii) where CMA/karyotyping was negative. PROSPERO No. CRD42019140309. / RESULTS: In our cohort ES gave an additional diagnostic yield in; (i) all CHD; (ii) isolated CHD and; (iii) multi‐system CHD of 12.7% (n=25/197), 11.5% (n=14/122) and 14.7% (n=11/75) (p=0.81). The pooled incremental yields for the aforementioned categories from 18‐studies (n=636) were 21% (95% CI, 15‐27%), 11% (95% CI, 7‐15%) and 37% (95% CI, 18%‐56%) respectively. This did not differ significantly when sub‐analyses were limited to studies including >20 cases. In instances of multi‐system CHD in the primary analysis, the commonest extra‐cardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system 44.2% (n=23/52). Cardiac shunt lesions had the greatest incremental yield, 41% (95% CI, 19‐63%), followed by right‐sided lesions 26% (95% CI, 9‐43%). In the majority of instances pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes (68/96; 70.8%). The commonest monogenic syndrome identified was Kabuki syndrome (n=19/96; 19.8%). / CONCLUSIONS: Despite the apparent incremental yield of prenatal exome sequencing in congenital heart disease, the routine application of such a policy would require the adoption of robust bioinformatic, clinical and ethical pathways. Whilst the greatest yield is with multi‐system anomalies, consideration may also be given to performing ES in the presence of isolated cardiac abnormalities

Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

Objective: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and investigate factors which increase diagnostic yield. Design: Retrospective analysis of data from two prospective cohort studies. Setting: Fetal medicine centres in the UK and USA. Population: Fetuses with increased NT ≥3.5mm at 11-14 weeks’ gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal WES studies (n = 213). Methods: We grouped cases based on (i) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (ii) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. Main Outcome Measures: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. Results: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. Conclusions: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE) study: prospective cohort study and systematic review.

OBJECTIVE: To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD). METHODS: A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup. RESULTS: In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15-27%), 11% (95% CI, 7-15%) and 37% (95% CI, 18-56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17-80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19-63%)), followed by right-sided lesions (26% (95% CI, 9-43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome. CONCLUSIONS: There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd

Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology

Male breast cancer

Male breast cancer (MBC) is a rare disease representing less than 1% of all breast cancers (BC) and less than 1% of cancers in men. Age at presentation is mostly in the late 60s. MBC is recognized as an estrogen-driven disease, specifically related to hyperestrogenism. About 20% of MBC patients have family history for BC. Mutations in BRCA1 and, predominantly, BRCA2, account for approximately 10% of MBC cases. Because of its rarity, MBC is often compared with female BC (FBC). Based on age-frequency distribution, age-specific incidence rate patterns and prognostic factors profiles, MBC is considered similar to late-onset, postmenopausal estrogen/progesterone receptor positive (ER+/PR+) FBC. However, clinical and pathological characteristics of MBC do not exactly overlap FBC. Compared with FBC, MBC has been reported to occur later in life, present at a higher stage, and display lower histologic grade, with a higher proportion of ER+ and PR+ tumors. Although rare, MBC remains a substantial cause for morbidity and mortality in men, probably because of its occurrence in advanced age and delayed diagnosis. Diagnosis and treatment of MBC generally is similar to that of FBC. Men tend to be treated with mastectomy rather than breast-conserving surgery. The backbone of adjuvant therapy or palliative treatment for advanced disease is endocrine, mostly tamoxifen. Use of FBC-based therapy led to the observation that treatment outcomes for MBC are worse and that survival rates for MBC do not improve like FBC. These different outcomes may suggest a non-appropriate utilization of treatments and that different underlying pathogenetic mechanisms may exist between male and female BC