Search

Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly., Competing Interests: Competing interests: P.T.E. has received sponsored research support from Bayer AG, IBM Health, Bristol Myers Squibb and Pfizer; he has consulted for Bayer AG, Novartis and MyoKardia. K.G.A. has received sponsored research support from Sarepta Therapeutics and Bayer AG, and reports a research collaboration with Novartis. Y.M.P. is involved in the development of therapies for DCM as an advisor to Forbion and Medical Director at ARMGO pharma and CMO at Phlox Therapeutics. P.C. reports personal fees for consultancies, outside the present work, for Amicus, OWKIN, Pfizer and SANOFI. J.S.W. has received research support from Bristol Myers Squibb, and has acted as a consultant for MyoKardia, Pfizer, Foresite Labs, Health Lumen and Tenaya Therapeutics. The remaining authors declare no competing interests., (© 2024. The Author(s).)

The recently developed metabolically more stable minigastrin derivative, DOTA-CCK-66, displayed promising preclinical data when labeled either with 68 Ga or 177 Lu. First positron emission tomography/computed tomography (PET/CT) imaging using [ 68 Ga]Ga-DOTA-CCK-66 in two patients suffering from medullary thyroid carcinoma (MTC) displayed a favorable biodistribution profile. Here, we aim to investigate the therapeutic potential of [ 225 Ac]Ac-DOTA-CCK-66 as a targeted α-therapy (TAT) agent in a comparative treatment study of [ 177 Lu]Lu- versus [ 225 Ac]Ac-DOTA-CCK-66., Methods: Treatment studies were performed (3 groups, n = 5, AR42J tumor-bearing 394-NOD SCID mice). Control group animals were injected with [ 68 Ga]Ga-DOTA-CCK-66 (1.1 MBq, PET/CT imaging), while treatment group animals received a single dose of either [ 177 Lu]Lu-DOTA-CCK-66 (37 MBq, radioligand therapy (RLT)) or [ 225 Ac]Ac-DOTA-CCK-66 (37 kBq, TAT). All animals' tumor volume and body weight were monitored twice a week until end-point criteria were reached. Blood samples were evaluated (VetScan VS2, Abaxis) once mice were sacrificed., Results: Upon treatment, an initial decline in tumor volume, followed by a significantly delayed tumor growth of treated cohorts, was observed. Mean survival of 177 Lu- as well as 225 Ac-treated animals was increased by 3- (37 ± 3 d) and 4.5-fold (54 ± 6 d), respectively, when compared to non-treated animals (12 ± 3 d). Blood sample analysis did not indicate toxic side effects to the liver, kidney, or stomach upon 177 Lu and 225 Ac-treatment., Conclusion: We demonstrated a substantial therapeutic efficacy of 177 Lu- and 225 Ac-labeled DOTA-CCK-66. As expected, treatment with the latter resulted in the highest mean survival rates. These results indicate a high therapeutic potential of 225 Ac-labeled DOTA-CCK-66 for TAT in MTC patient management., (© 2024. The Author(s).)

Although women are well-represented in medical schools, they have remained a significant minority in radiology, with little recent progress made in bridging the gender gap. Underrepresentation of women is even more pronounced in radiology leadership and research positions, a phenomenon termed the "leaky pipeline." We aim to present the root causes of female underrepresentation in radiology based on existing literature and propose specific interventions for this issue based on engaging female medical students in radiology education. Factors contributing to the so-called leaky pipeline can be categorized as underexposure to radiology and preconceived notions, female disinterest in radiology, lack of mentorship, and female underrepresentation in academic authorship and leadership roles. We propose that combined application of early engagement of female medical students in radiology, increasing available female mentorship, and increased female visibility in the field will serve as an effective approach toward the complex, multifactorial problem of female underrepresentation in radiology., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Inc.)

Objectives: To evaluate the impact of aspirin resistance on the incidence of preeclampsia and maternal serum biomarker levels in pregnant individuals at high-risk of preeclampsia receiving low dose aspirin (LDA)., Study Design: We performed a secondary analysis of a randomized, placebo-controlled trial of LDA (60 mg daily) for preeclampsia prevention in high-risk individuals (N = 524) on pregnancy outcomes and concentrations of PLGF, IL-2, IL-6, thromboxane B2 (TXB 2 ), sTNF-R1 and sTNF-R2 from maternal serum., Main Outcome Measures: LDA-resistant individuals were defined as those having a TXB 2 concentration >10 ng/ml or <75 % reduction in concentration at 24-28 weeks after LDA administration. Comparisons of outcomes were performed using a Fisher's Exact Test. Mean concentrations of maternal serum biomarkers were compared using a Student's t-test. Pearson correlation was calculated for all pairwise biomarkers. Longitudinal analysis across gestation was performed using linear mixed-effects models accounting for repeated measures and including BMI and maternal age as covariates., Results: We classified 60/271 (22.1 %) individuals as LDA-resistant, 179/271 (66.1 %) as LDA-sensitive, and 32/271 (11.8 %) as non-adherent. The prevalence of preeclampsia was not significantly different between the LDA and placebo groups (OR = 1.43 (0.99-2.28), p-value = 0.12) nor between LDA-sensitive and LDA-resistant individuals (OR = 1.27 (0.61-2.8), p-value = 0.60). Mean maternal serum IL-2 concentrations were significantly lower in LDA-resistant individuals relative to LDA-sensitive individuals (FDR < 0.05)., Conclusions: These results suggest a potential role for IL-2 in the development of preeclampsia modulated by an individuals' response to aspirin, presenting an opportunity to optimize aspirin prophylaxis on an individual level to reduce the incidence of preeclampsia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation., Methods: The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted., Results: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months., Discussion: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past., (© 2024. The Author(s).)

Objective: The objectives of this study were to determine the richness, abundance, and diversity of bacteria in stray dogs ( Canis lupus familiaris ) infested by ticks in Comarca Lagunera, northern Mexico, and to establish their pathogenic and or/zoonotic potential., Materials and Methods: Blood samples from 12 dogs were collected, and their deoxyribonucleic acid was extracted. The V3-V4 region of the 16S ribosomal ribunocleic acid gene was amplified by polymerase chain reaction. Next-generation sequencing (NGS) was performed on a MiSeq Illumina platform, and the data were analyzed using quantitative insights into microbial ecology., Results: The operational taxonomic units resulted in 23 phyla, 54 classes, 89 orders, 189 families, 586 genera, and 620 bacterial species; among them, 64 species and/or bacterial genera with pathogenic or zoonotic potential were identified, some of which have been reported in the literature as relevant to public health ( Anaplasma phagocytophilum, Brucella spp ., Clostridium spp ., Corynebacterium affermentants, Cutibacterium spp ., Dietzia spp ., Ehrlichia canis, Fusobacterium necrophorum, Leptotrichia spp ., Mycobacterium spp ., Paracoccus spp ., and Roseomonas gilardii )., Conclusion: This research offers relevant information on the prevalence of tick-borne diseases as well as other potential zoonotic diseases in the blood of stray dogs parasitized by ticks in northern Mexico. New molecular biology and massive NGS techniques may play an important role in the study and documentation of bacterial profiles from animals in close proximity to humans., Competing Interests: The authors declare no conflict of interest., (Copyright: © Journal of Advanced Veterinary and Animal Research.)

Background: Studies that have assessed the Rastelli and Nikaidoh operations for transposition of the great arteries (TGA) with obstructed left ventricular outflow tract obstruction (LVOTO) have not fully evaluated the anatomic drivers that may contribute to surgical selection. We present our procedural selection process for optimizing outcomes of complex TGA in the modern era., Methods: This is a single-center, retrospective study that included pediatric patients who underwent either a Nikaidoh or Rastelli operation for the treatment of TGA-LVOTO, congenitally corrected TGA-LVOTO, or double-outlet right ventricle TGA type-LVOTO from June 2004 to June 2021., Results: There were 34 patients stratified by Nikaidoh (n = 16) or Rastelli (n = 18) operation. The incidence of all postoperative complications and mortality was low, and the incidence of complications between the groups was similar. Patients were more likely to have undergone a Nikaidoh than a Rastelli if they had a pulmonary annulus >5 mm (87.5% vs 11.1%), anteriorly/posteriorly oriented great vessels (88% vs 8%), remote (80% vs 11%) or restrictive (75% vs 6%) ventricular septal defect, and right ventricular hypoplasia (50% vs 0%; all, P < .05). The resulting rates of reoperation were similar between the groups (44.0% vs 37.5%; P = .24) and largely composed of conduit replacements in the Rastelli patients and valvular repairs or replacements in the Nikaidoh group. Rates of catheter-based interventions were also similar., Conclusions: These findings suggest that for the optimal treatment of conotruncal anomalies with discordant ventriculoarterial connections, procedural selection should be based on pathoanatomic criteria that can ensure patients undergo the operation most suited to their anatomy., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Aims: The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing., Methods and Results: In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels., Conclusion: Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI., Competing Interests: Conflict of interest: S.K. declares research grants from the Swiss Heart Foundation, the Lindenhof Foundation, the Novartis Foundation for Medical-biological Research, the Swiss Society of Cardiology, the Jubiläumsstiftung SwissLife and the Theodor-Ida-Herzog-Egli Foundation, and equipment and materials from Roche Diagnostics outside the submitted work. Further, he has received travel support from the European Atherosclerosis Society, the European Society of Cardiology, the European Society of Clinical Investigation, Sphingotec GmbH, the 4TEEN4 Pharmaceuticals GmbH, and PAM Theragnostics GmbH. T.F.L. has no conflicts of interest related to this manuscript but has received institutional educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Vifor and consulting fees from Daiichi Sankyo, Ineeo Inc., Philips, and Pfizer outside the submitted work. T.F.L. holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. G.G.C. and L.L. are co-inventors on the international patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of I/R injury to the central nervous system. G.G.C. is a consultant to Sovida Solutions Limited. L.L. reports speaker fees outside of this work from Daiichi Sankyo. F.A.W. received travel support by 4TEEN4 Pharmaceuticals GmbH, PAM Theragnostics GmbH, and Sphingotec GmbH. L.R. received research grants by Abbott, Biotronik, Boston Scientific, HeartFlow, Infraredx, Sanofi, and Regeneron and reports consultation/advisory board fees by Abbott, AstraZeneca, Amgen, Canon, Novo Nordisk, Medtronic, and Occlutech. C.M.M. has received research grants to the institution from Eli Lilly, AstraZeneca, Roche, Amgen, Novartis, Novo Nordisk, and MSD including speaker or consultant fees., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [ 177 Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [ 177 Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [ 177 Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [ 177 Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [ 177 Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [ 177 Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [ 177 Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177 Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Post transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid proliferations in recipients of solid organs which seem to be related to Epstein Barr Virus (EBV). The use of antilymphocyte antibodies, EBV seronegativity in the recipient,acute rejection and CMV infection have been identified as classical risk factors., Material Y Methods: We have studied in a retrospective observational study, the incidence of PTLD in a period of 22 years, its relationship with EBV, presence of classical risk factors and outcome in 21546 simple adult renal transplant recipients from cadaveric and living donors, transplanted in 21 hospitals from 1990 to 2009., Results: A total of 275 recipients developed PTLD (1,2%),195 males (70,9%), 80 females (29,1%) aged 59.2 (p25 44.7 p75 68)years. Two hundred forty-five (89.0%) were 1st transplant recipients and 269 (97,8%) from cadaveric donors. EBV in the tissue was reported in 94 out of the 155 studied recipients (60.6%) and 86.0% of the proliferations were due to B lymphocytes. PTLD median appearance after transplant were 42.months (p25, 75, 12, 77, 5). One hundred eighty-eight recipients out of 275 patients (68.3%) had any classical risk factor and the use of antilymphocyte antibodies was the most frequent. During the follow-up, 172 patients died (62,5%) and 103 (37,5%) had a complete remission. The main cause of death was PTLD progression (n = 91, 52,9%), followed by sepsis (n = 24, 13,9%). The follow-up period post-transplant of the recipients was between 3 and 22 years. The incidence was 0,14% during the first year post-trasplant and 0.98% the cumulative incidence at 10 years. Patient survival after diagnosis was 51%, 44% and 39% after 1, 2 and 5 years, respectively. Finally, overall graft survival was 48%, 39% and 33% at the same periods., Conclusion: PTLD has a low incidence in renal transplant recipients. Most of the proliferations are due to B lymphocytes and seem to have a close relationship with EBV. PTLD can develop in the absence of classical risk factors. The prognosis is poor, mainly due to PTLD progression, but the survivors can even maintain their grafts., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: Incorporating human behavior in a disease model can explain the oscillations in COVID-19 data which occur more rapidly than can be explained by variants alone on college campuses., Methods: Dampened oscillations emerge by supplementing a simple disease model with a risk assessment function, which depends on the current number of infected individuals in the student population and the institutional public health policies. After accounting for a rapid disease impulse due to social gatherings, we achieve sustained oscillations that follow the trend of 2020/2021 COVID-19 data as reported on the COVID-19 dashboards of US post-secondary institutions., Results: This adjustment to the epidemiological model can provide an intuitive way of understanding rapid oscillations based on human risk perception and institutional policies. More risk-averse communities experience lower disease-level equilibria and less oscillations within the system, while communities that are less responsive to changes in the number of infected individuals exhibit larger amplitude and frequency of the oscillations., Conclusions: Community risk assessment plays an important role in COVID-19 management in college settings. Improving the ability of individuals to rapidly and conservatively respond to changes in community disease levels may help assist in self-regulating these oscillations to levels well below thresholds for emergency management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Prostate cancer is the leading cancer in incidence and second leading cause of cancer mortality in US men. African American men have significantly higher incidence and mortality rates from prostate cancer than European American men. Previous studies reported that the disparity in prostate cancer survival or mortality can be explained by different biological backgrounds. microRNAs (miRNAs) regulate gene expression of their cognate mRNAs in many cancers. Therefore, miRNAs may be a potentially promising diagnostic tool. The role of miRNAs in prostate cancer aggressiveness and racial disparity has not been fully established. The goal of this study is to identify miRNAs associated with aggressiveness and racial disparity in prostate cancer. Here we report miRNAs that are associated with tumor status and aggressiveness in prostate cancer using a profiling approach. Further, downregulated miRNAs in African American tissues were confirmed by qRT-PCR. These miRNAs have also been shown to negatively regulate the expression of the androgen receptor in prostate cancer cells. This report provides a novel insight into understanding tumor aggressiveness and racial disparities of prostate cancer.

Radiation therapy induces targeted effects in the cells that are irradiated and also non-targeted effects (i.e. bystander effects) in non-irradiated cells that are close to or at short distance (<∼1 mm) from irradiated cells. Bystander effects are mediated by intercellular communications and may result in cytotoxic and genotoxic modifications. Their occurrence and relative contribution to the irradiation outcome are influenced by several parameters among which the particle linear energy transfer seems to be prominent. Bystander effects were first observed after external radiation therapy, but have been described also following targeted radionuclide therapy. Therefore, we propose a method to investigate their occurrence in experimental conditions where cells are exposed to radiopharmaceuticals. In this approach, clonogenic cell death is the biological endpoint of the bystander effects caused by irradiation with alpha particles (a potent inducer of the bystander response)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In a previous work, an IL-2Rβγ biased mutant derived from human IL-2 and called IL-2noα, was designed and developed. Greater antitumor effects and lower toxicity were observed compared to native IL-2. Nevertheless, mutein has some disadvantages, such as a very short half-life of about 9-12 min, propensity for aggregation, and solubility problems., Objective: In this study, PEGylation was employed to improve the pharmacokinetic and antitumoral properties of the novel protein., Methods: Pegylated IL-2noα was characterized by polyacrylamide gel electrophoresis, size exclusion chromatography, in vitro cell proliferation and in vivo cell expansion bioassays, and pharmacokinetic and antitumor studies., Results: IL-2noα-conjugates with polyethylene glycol (PEG) of 1.2 kDa, 20 kDa, and 40 kDa were obtained by classical acylation. No significant changes in the secondary and tertiary structures of the modified protein were detected. A decrease in biological activity in vitro and a significant improvement in half-life were observed, especially for IL-2noα-PEG20K. PEGylation of IL-2noα with PEG20K did not affect the capacity of the mutant to induce preferential expansion of T effector cells over Treg cells. This pegylated IL-2noα exhibited a higher antimetastatic effect compared to unmodified IL-2noα in the B16F0 experimental metastases model, even when administered at lower doses and less frequently., Conclusion: PEG20K was selected as the best modification strategy, to improve the blood circulation time of the IL-2noα with a superior antimetastatic effect achieved with lower doses., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Calcium intake remains inadequate in many low- and middle-income countries, especially in Africa and South Asia, where average intakes can be below 400 mg/day. Given the vital role of calcium in bone health, metabolism, and cell signaling, countries with low calcium intake may want to consider food-based approaches to improve calcium consumption and bioavailability within their population. This is especially true for those with low calcium intake who would benefit the most, including pregnant women (by reducing the risk of preeclampsia) and children (by reducing calcium-deficiency rickets). Specifically, some animal-source foods that are naturally high in bioavailable calcium and plant foods that can contribute to calcium intake could be promoted either through policies or educational materials. Some food processing techniques can improve the calcium content in food or increase calcium bioavailability. Staple-food fortification with calcium can also be a cost-effective method to increase intake with minimal behavior change required. Lastly, biofortification is currently being investigated to improve calcium content, either through genetic screening and breeding of high-calcium varieties or through the application of calcium-rich fertilizers. These mechanisms can be used alone or in combination based on the local context to improve calcium intake within a population., (© 2021 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

In 2021, approximately 248,530 new prostate cancer (PCa) cases are estimated in the United States. Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. The objective of this study was to assess DNA methylation patterns between aggressive and indolent PCa along with ancestry proportions in 49 H/L men from Puerto Rico (PR). Prostate tumors were classified as aggressive ( n = 17) and indolent ( n = 32) based on the Gleason score. Genomic DNA samples were extracted by macro-dissection. DNA methylation patterns were assessed using the Illumina EPIC DNA methylation platform. We used ADMIXTURE to estimate global ancestry proportions. We identified 892 differentially methylated genes in prostate tumor tissues as compared with normal tissues. Based on an epigenetic clock model, we observed that the total number of stem cell divisions (TNSC) and stem cell division rate (SCDR) were significantly higher in tumor than adjacent normal tissues. Regarding PCa aggressiveness, 141 differentially methylated genes were identified. Ancestry proportions of PR men were estimated as African, European, and Indigenous American; these were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation profiles associated with risk and aggressiveness of PCa in PR H/L men will shed light on potential mechanisms contributing to PCa disparities in PR population.

Background: The consequences of the earth's daily rotation have led to 24-h biological rhythms in most organisms. Even some parasites are known to have daily rhythms, which, when in synchrony with host rhythms, can optimise their fitness. Understanding these rhythms may enable the development of control strategies that take advantage of rhythmic vulnerabilities. Recent work on protozoan parasites has revealed 24-h rhythms in gene expression, drug sensitivity and the presence of an intrinsic circadian clock; however, similar studies on metazoan parasites are lacking. To address this, we investigated if a metazoan parasite has daily molecular oscillations, whether they reveal how these longer-lived organisms can survive host daily cycles over a lifespan of many years and if animal circadian clock genes are present and rhythmic. We addressed these questions using the human blood fluke Schistosoma mansoni that lives in the vasculature for decades and causes the tropical disease schistosomiasis., Results: Using round-the-clock transcriptomics of male and female adult worms collected from experimentally infected mice, we discovered that ~ 2% of its genes followed a daily pattern of expression. Rhythmic processes included a stress response during the host's active phase and a 'peak in metabolic activity' during the host's resting phase. Transcriptional profiles in the female reproductive system were mirrored by daily patterns in egg laying (eggs are the main drivers of the host pathology). Genes cycling with the highest amplitudes include predicted drug targets and a vaccine candidate. These 24-h rhythms may be driven by host rhythms and/or generated by a circadian clock; however, orthologs of core clock genes are missing and secondary clock genes show no 24-h rhythmicity., Conclusions: There are daily rhythms in the transcriptomes of adult S. mansoni, but they appear less pronounced than in other organisms. The rhythms reveal temporally compartmentalised internal processes and host interactions relevant to within-host survival and between-host transmission. Our findings suggest that if these daily rhythms are generated by an intrinsic circadian clock then the oscillatory mechanism must be distinct from that in other animals. We have shown which transcripts oscillate at this temporal scale and this will benefit the development and delivery of treatments against schistosomiasis., (© 2021. The Author(s).)

Facial palsy is a common neurologic concern and is the most common cranial neuropathy. The facial nerve contains motor, parasympathetic, and special sensory functions. The most common form of facial palsy is idiopathic (Bell's palsy). A classic presentation requires no further diagnostic measures, and generally improves with a course of corticosteroid and antiviral therapy. If the presentation is atypical, or concerning features are present, additional studies such as brain imaging and cerebrospinal fluid analysis may be indicated. Many conditions may present with facial weakness, either in isolation or with other neurologic signs (e.g., multiple cranial neuropathies). The most important ones to recognize include infections (Ramsay-Hunt syndrome associated with herpes zoster oticus, Lyme neuroborreliosis, and complications of otitis media and mastoiditis), inflammatory (demyelination, sarcoidosis, Miller-Fisher variant of Guillain-Barré syndrome), and neoplastic. No matter the cause, individuals may be at risk for corneal injury, and, if so, should have appropriate eye protection. Synkinesis may be a bothersome residual phenomenon in some individuals, but it has a variety of treatment options including neuromuscular re-education and rehabilitation, botulinum toxin chemodenervation, and surgical intervention., Competing Interests: None declared., (Thieme. All rights reserved.)

Electronic cigarettes (e-cigarettes) or vaping use in adolescents has emerged as a public health crisis that impacts the perioperative care of this vulnerable population. E-cigarettes have become the most commonly used tobacco products among youth in the United States. Fruit and mint flavors and additives such as marijuana have enticed children and adolescents. E-cigarette, or vaping, product use-associated lung injury (EVALI) is a newly identified lung disease linked to vaping. Clinical presentation of EVALI can be varied, but most commonly includes the respiratory system, gastrointestinal (GI) tract, and constitutional symptoms. Clinical management of EVALI has consisted of vaping cessation and supportive therapy, including supplemental oxygen, noninvasive ventilation, mechanical ventilation, glucocorticoids, and empiric antibiotics, until infectious causes are eliminated, and in the most severe cases, extracorporeal membrane oxygenation (ECMO). Currently, although there is an insufficient evidence to determine the safety and the efficacy of e-cigarettes for perioperative smoking cessation, EVALI clearly places these patients at an increased risk of perioperative morbidity. Given the relatively recent introduction of e-cigarettes, the long-term impact on adolescent health is unknown. As a result, the paucity of postoperative outcomes in this potentially vulnerable population does not support evidence-based recommendations for the management of these patients. Clinicians should identify "at-risk" individuals during preanesthetic evaluations and adjust the risk stratification accordingly. Our societies encourage continued education of the public and health care providers of the risks associated with vaping and nicotine use and encourage regular preoperative screening and postoperative outcome studies of patients with regard to smoking and vaping use., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Background: Trisomy 18 or Edwards syndrome is the second most common aneuploidy with a prevalence between 1/3000 and 1/10 000 live births. The syndrome encompasses malformations of the central nervous, cardiac, respiratory, gastrointestinal, and genitourinary systems. Trisomy 18 carries a poor prognosis with 90% of patients not surviving beyond 1 year of age; however, the current trend toward more aggressive supportive care may prolong survival. The limited anesthesia literature highlights the abnormal airway anatomy but generally describes uneventful airway management and perioperative course., Aim: Our goal was to review all anesthesia encounters recorded for eleven trisomy 18 patients treated at Children's Wisconsin during the study period to explore the frequency of anesthesia encounters and to improve our understanding of the perioperative risks., Methods: We performed a retrospective chart review of all patients with trisomy 18 who were treated at our institution between 2012 and 2017. Records were screened for anesthesia encounters, perioperative critical events and complications, enrollment in palliative care, code status, and time of death., Results: Eleven children were identified. Children were born between 2001 and 2016. Two children never required anesthesia care. Nine patients had a total of 84 anesthesia encounters for 121 surgical or diagnostic procedures or emergent intubations. Critical events and perioperative complications included difficult mask ventilation (n = 7), difficult intubation (n = 15), and mechanical or pharmacological cardiopulmonary resuscitation (n = 6). Five patients presented with difficult peripheral intravenous access. One patient died in the immediate postoperative period. On five occasions, patients required emergent intubation outside of the operating room., Conclusion: Difficult airway management and respiratory compromise were critical concerns during the perioperative period in our patient population, and the inability to ventilate could lead to cardiorespiratory arrest. This case series provides a comprehensive, longitudinal view of complete trisomy 18 patients in the perioperative period and adds information for counseling families and care providers., (© 2021 John Wiley & Sons Ltd.)

Over the past four decades, there have been progressive changes in the epidemiology of traumatic spinal cord injury (tSCI). We assessed trends in demographic and injury-related variables in traumatic cervical spinal cord injury (tCSCI) patients over an 18-year period at a single Level I trauma center. We included all magnetic resonance imaging-confirmed tCSCI patients ≥15 years of age for years 2001-2018. Among 1420 patients, 78.3% were male with a mean age 51.5 years. Etiology included falls (46.9%), motor vehicle collisions (MVCs; 34.2%), and sports injuries (10.9%). Median American Spinal Injury Association (ASIA) Motor Score (AMS) was 44, complete tCSCI was noted in 29.6% of patients, fracture dislocations were noted in 44.7%, and median intramedullary lesion length (IMLL) was 30.8 mm (complete injuries 56.3 mm and incomplete injuries 27.4 mm). Over the study period, mean age and proportion of falls increased ( p  < 0.001) whereas proportion attributable to MVCs and sports injuries decreased ( p  < 0.001). Incomplete injuries, AMS, and the proportion of patients with no fracture dislocations increased whereas complete injuries decreased significantly. IMLL declined ( p  = 0.17) and proportion with hematomyelia did not change significantly. In adjusted regression models, increase in age and decreases in prevalence of MVC mechanism and complete injuries over time remained statistically significant. Changes in demographic and injury-related characteristics of tCSCI patients over time may help explain the observed improvement in outcomes. Further, improved clinical outcomes and drop in IMLL may reflect improvements in initial risk assessment and pre-hospital management, advances in healthcare delivery, and preventive measures including public education.

The next generation of life science professionals will require far more quantitative skills than prior generations. Calculus is important for understanding dynamical systems in biology and, therefore, is often a required course for life science students. However, many life science students do not understand the utility value of mathematics to biology. Therefore, according to expectancy-value theory, life science students may experience lower motivation, which can impact their performance in a calculus course. This study examines how two different biocalculus courses, which integrated calculus and biological concepts and successfully halved the rates of students earning a D, F, or withdrawing (DFW), affected life science students' utility value, interest, and overall attitudes toward mathematics. Using pre and post surveys, we found that students' interest in mathematics increased by the end of the semester, and they demonstrated a more sophisticated understanding of how mathematics is used in biology. Students whose attitudes toward mathematics improved primarily attributed these changes to a better understanding of the utility of mathematics to biology, feelings of competence in mathematics, or rapport with the instructor. Thus, communicating the utility value of mathematics to biology through integrated mathematics-biology courses can contribute to improved attitudes toward mathematics that can impact students' motivation and performance.

As we strive to lift up a diversity of voices in science, it is important for ecologists, evolutionary scientists, and educators to foster inclusive environments in their research and teaching. Academics in science often lack exposure to research on best practices in diversity, equity, and inclusion and may not know where to start to make scientific environments more welcoming and inclusive. We propose that by approaching research and teaching with empathy, flexibility, and a growth mind-set, scientists can be more supportive and inclusive of their colleagues and students. This paper provides guidance, explores strategies, and directs scientists to resources to better cultivate an inclusive environment in three common settings: the classroom, the research laboratory, and the field. As ecologists and evolutionary scientists, we have an opportunity to adapt our teaching and research practices in order to foster an inclusive educational ecosystem for students and colleagues alike., Competing Interests: None declared., (© 2020 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Women who experience intimate partner violence (IPV) face multiple barriers to seeking help from community resources, but little research has examined the impact of ecological influences on community resource utilisation among women living in low- and middle-income countries. The current study investigated individual-, relationship-, family-, and community-level influences on community resource utilisation among Mexican women experiencing IPV. Using baseline data from 950 women in Mexico City enrolled in a clinic-based randomised controlled trial, multilevel regressions were performed to assess associations between socioecological factors and women's community resource utilisation. 41.3% women used at least one resource. At the individual-level, every additional resource that women were aware of, was associated with a 20% increase in the total number of resources used ( p  < .001). Every additional lethal risk factor was associated with a 5% increase in the total number of resources used ( p  = .004). At the family-level, women who reported having an in-law encourage IPV used 46% more resources ( p  < .001). At the community-level, stronger supportive norms around community resource utilisation was associated with a 6% increase in the total number of resources ( p  = .01). These findings suggest the importance of addressing family and community factors in the broader ecological context of Mexican women's help-seeking behaviours.

The developing brain undergoes drastic alterations. Here, we investigated developmental changes in the habenula, a brain region that mediates behavioral flexibility during learning, social interactions, and aversive experiences. We showed that developing habenular circuits exhibit multiple alterations that lead to an increase in the structural and functional diversity of cell types, inputs, and functional modules. As the habenula develops, it sequentially transforms into a multisensory brain region that can process visual, olfactory, mechanosensory, and aversive stimuli. Moreover, we observed that the habenular neurons display spatiotemporally structured spontaneous activity that shows prominent alterations and refinement with age. These alterations in habenular activity are accompanied by sequential neurogenesis and the integration of distinct neural clusters across development. Last, we revealed that habenular neurons with distinct functional properties are born sequentially at distinct developmental time windows. Our results highlight a strong link between the functional properties of habenular neurons and their precise birthdate., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman-Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I-IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8-10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8-73.4) and 19.8% (95% CI 10.8-30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.

Starting in the early 2000's, several reports were released recognizing the convergence of mathematics, biology and computer science, and calling for a rethinking of how undergraduates are prepared for careers in research and the science and technology workforce. This call for change requires careful consideration of the mathematical biology education system to identify key components and leverage points for change. This paper demonstrates the wide range of resources and approaches available to the mathematical biology education community to create systemic change by highlighting the efforts of four community-based education reform organizations. A closer look at these organizations provides an opportunity to examine how to leverage components of the education system including faculty, academic institutions, students, access to resources, and the power of community.

Background: Beginning June 2019, Children's Wisconsin was the first hospital to identify a cohort of adolescent patients hospitalized with symptoms likely associated with e-cigarette use. Our report adds to the growing literature describing the radiographic, gross and cytopathologic bronchoscopic findings, and short-term lung function outcomes in this cohort of adolescents with e-cigarette or vaping product use associated lung injury (EVALI)., Methods: We present 15 adolescents hospitalized from June to September, 2019 with confirmed EVALI. We abstracted data from inpatient hospitalization and first outpatient pulmonary clinic visit., Results: There were 15 patients (11 male, 12 White) with a mean age of 17.1 years. All patients presented with subacute pulmonary, gastrointestinal and constitutional complaints. Diagnostic workup was guided by the Centers for Disease Control criteria for confirmed EVALI case surveillance. Flexible bronchoscopy was performed in 13/15 patients with 10/13 demonstrating gross pathologic abnormalities. Seven of 15 patients required intensive care and 2 met criteria for pediatric Acute Respiratory Distress Syndrome. Patients had dramatic improvement with systemic glucocorticoid therapy and 14/15 were discharged on room air. Eleven patients were seen as outpatients. Despite 11/11 patients reporting resolved or improved symptoms, 7/11 had abnormalities on pulmonary function testing. We initiated inhaled corticosteroids for 5/11 patients and 4/11 patients remained on their corticosteroid wean., Conclusions and Relevance: We report short-term outcomes of the first cohort of adolescent patients hospitalized with EVALI. An association is observed between clinical improvement and treatment with systemic corticosteroids. However, residual airway reactivity or diffusion abnormalities persisted when patients were re-evaluated in the short-term period (mean 4.5 weeks)., (© 2020 Wiley Periodicals, Inc.)

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

E-cigarette, or vaping, product use has been declared an epidemic, and a new disease has emerged from their use. We describe 4 patients with significant acute lung injury related to e-cigarette use who underwent bronchoscopy and bronchoalveolar lavage. All cases posed anesthetic challenges, including increased airway reactivity, hypoxia, increasing oxygen requirements, and, in 2 severe cases, the need for continued postprocedural mechanical ventilatory support. It is imperative that all members of the treating team are aware of the disproportionate risk of respiratory complications to anticipate the possible need for increased postprocedural respiratory support.

Introduction: Few studies have investigated how intimate partner violence (IPV), and patterns of IPV experiences, may impact children's school attendance in low- and middle-income countries., Methods: Using baseline data from a sub-sample of 659 women in Mexico City enrolled in a randomized controlled trial who reported having a child under age 18 and in school, multilevel latent class analysis (LCA) was used to classify women based on their reported IPV experiences. Multilevel risk regression analyses examined associations between latent class membership and IPV-related disruptions in children's schooling. Latent classes were identified in a prior study., Results: Overall, 23.3% of women reported their child's school attendance was disrupted due to IPV. LCA identified four distinct classes of IPV experiences: Low Physical and Sexual Violence (39.1%); Low Physical and High Sexual Violence class (14.8%), High Physical and Low Sexual Violence and Injuries (36.5%); and High Physical and Sexual Violence and Injuries (9.6%). Compared with women in the Low Physical and Sexual Violence class, women in the High Physical and Sexual Violence and Injuries class and women in the High Physical and Low Sexual Violence and Injuries class were at greater risk of IPV disrupting children's school attendance (ARR 3.39, 95% CI 2.34, 4.92; ARR 2.22, 95% CI 1.54, 3.19, respectively). No other statistically significant associations emerged., Discussion: High disruptions in children's school attendance due to IPV were reported and were differentially related to patterns of IPV experiences. Findings underscore the need to understand underlying mechanisms. Future work integrating both violence against women and violence against children is needed.

von Willebrand disease is a common bleeding disorder, but diagnosis can be difficult in young children who have not had bleeding challenges. We sought to evaluate the correlation between bleeding and von Willebrand factor (VWF) levels in children undergoing surgical challenge with tonsillectomy. Children ages 0 to 18 undergoing tonsillectomy without a personal or family history of bleeding were enrolled prospectively following informed consent and institutional review board approval. VWF levels were obtained at the time of surgery. VWF antigen (VWF:Ag) and VWF activity (VWF:GPIbM) were tested via enzyme-linked immunosorbent assay. Bleeding score was calculated using the International Society of Hematology bleeding assessment tool (BAT). Surgical and postoperative bleeding were determined using questionnaires filled out by the surgeon and patient/family. A total of 1399 subjects were enrolled with evaluable data, with a median age of 5 years. The median VWF:Ag was 85 IU/dL and the median VWF:GPIbM was 100 U/dL. Median BAT for the entire population was 0, including those with postoperative bleeding. There was no difference in VWF level between those who experienced postoperative bleeding and those who did not, with median VWF:Ag 85 vs 85 (P = .89) and mean VWF:GPIbM 98 vs 100 (P = .5). Interestingly, there was a difference in VWF levels with age, with median VWF:Ag 81 for those younger than 3 years, 82 for those 3 to 6 years, 90 for those 7 to 10 years, and 100 for those 11 to 18 years. A similar trend was noted for VWF:GPIbM. Of the 2 to 6 year olds, 5% had VWF:Ag <50, which would meet criteria for low VWF, but only 1.8% had an abnormal BAT at study entry and only 2.5% bled after surgery. Only 1 subject with low VWF had an elevated postoperative BAT >2. These data suggest that low VWF levels do not correlate with bleeding in children undergoing tonsillectomy. In addition, VWF levels outside the adult normal range in young children may be more common than previously thought and do not necessarily predict surgical bleeding., (© 2020 by The American Society of Hematology.)

Quantum mechanics (QM) methods provide a fine description of receptor-ligand interactions and of chemical reactions. Their use in drug design and drug discovery is increasing, especially for complex systems including metal ions in the binding sites, for the design of highly selective inhibitors, for the optimization of bi-specific compounds, to understand enzymatic reactions, and for the study of covalent ligands and prodrugs. They are also used for generating molecular descriptors for predictive QSAR/QSPR models and for the parameterization of force fields. Thanks to the continuous increase of computational power offered by GPUs and to the development of sophisticated algorithms, QM methods are becoming part of the standard tools used in computer-aided drug design (CADD). We present the most used QM methods and software packages, and we discuss recent representative applications in drug design and drug discovery.

Background: A quadrivalent split-virion inactivated influenza vaccine (VaxigripTetra™, Sanofi Pasteur; IIV4) containing two A strains (H1N1 and H3N2) and B strains from both lineages (Victoria and Yamagata) was approved in Europe in 2016 for individuals aged ≥ 3 years. This study examined the efficacy and safety of IIV4 in children aged 6-35 months., Methods: This was a phase III randomised controlled trial conducted in Latin America, Asia, Africa, and Europe during the Northern Hemisphere 2014/2015 and 2015/2016 and Southern Hemisphere 2014 and 2015 influenza seasons. Healthy children aged 6-35 months not previously vaccinated against influenza were randomised to receive two full doses 28 days apart of IIV4, placebo, the licensed trivalent split-virion inactivated vaccine (IIV3), an investigational IIV3 containing a B strain from the alternate lineage. The primary objective was to demonstrate efficacy against influenza illness caused by any strain or vaccine-similar strains., Results: The study enrolled 5806 participants. Efficacy, assessed in 4980 participants completing the study according to protocol, was demonstrated for IIV4. Vaccine efficacy was 50.98% (97% CI, 37.36-61.86%) against influenza caused by any A or B type and 68.40% (97% CI, 47.07-81.92%) against influenza caused by vaccine-like strains. Safety profiles were similar for IIV4, placebo, and the IIV3s, although injection-site reactions were slightly more frequent for IIV4 than placebo., Conclusions: IIV4 was safe and effective for protecting children aged 6-35 months against influenza illness caused by vaccine-similar or any circulating strains., Clinical Trial Registration: EudraCT no. 2013-001231-51., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Endometriosis affects an estimated 10 percent of women and girls globally, yet little is known about symptoms and awareness among women in low- and middle-income countries. This commentary presents a descriptive secondary analysis of baseline data from a clinic-based intervention study with low-income women in Mexico City who experienced intimate partner violence in the past year(N = 754). The secondary analysis examined symptoms that may be suggestive of endometriosis as well as endometriosis awareness. Over half of participants reported at least one symptom suggestive of endometriosis (59.3 percent), while 12.5 percent of those reporting a symptom had ever heard of the disease. Pain-related symptoms were classified as pain with menses disrupting household chores, pain with menses disrupting work or social gatherings, and/or pelvic pain outside of menses disrupting daily activities. Fewer women who reported pain-related symptoms had heard of the disease compared to those who reported a history of infertility (11.4 vs. 15.7 percent, respectively).This study documents levels of awareness of endometriosis among women in Mexico City and underscores the importance of integrating endometriosis education into broader global reproductive health agendas.

Ornaments used in courtship often vary wildly among species, reflecting the evolutionary interplay between mate preference functions and the constraints imposed by natural selection. Consequently, understanding the evolutionary dynamics responsible for ornament diversification has been a longstanding challenge in evolutionary biology. However, comparing radically different ornaments across species, as well as different classes of ornaments within species, is a profound challenge to understanding diversification of sexual signals. Using novel methods and a unique natural history dataset, we explore evolutionary patterns of ornament evolution in a group-the birds-of-paradise-exhibiting dramatic phenotypic diversification widely assumed to be driven by sexual selection. Rather than the tradeoff between ornament types originally envisioned by Darwin and Wallace, we found positive correlations among cross-modal (visual/acoustic) signals indicating functional integration of ornamental traits into a composite unit-the "courtship phenotype." Furthermore, given the broad theoretical and empirical support for the idea that systemic robustness-functional overlap and interdependency-promotes evolutionary innovation, we posit that birds-of-paradise have radiated extensively through ornamental phenotype space as a consequence of the robustness in the courtship phenotype that we document at a phylogenetic scale. We suggest that the degree of robustness in courtship phenotypes among taxa can provide new insights into the relative influence of sexual and natural selection on phenotypic radiations., Competing Interests: The authors have declared that no competing interests exist.

Relapse of acute leukemia (AL) after allogeneic hematopoietic cell transplantation (Allo-HCT) entails a dismal prognosis. In this scenario, donor lymphocyte infusions (DLIs) and second Allo-HCT are two major approaches. We compared outcomes of AL patients treated for relapse with DLI or second Allo-HCT after receiving debulking therapy. In total, 46 patients were included in the study; 30 (65%) had acute myeloid leukemia and 16 (35%) had acute lymphoblastic leukemia. The median age was 38 years (range 4-66). Twenty-seven patients received a second Allo-HCT and 19 patients received DLI. The median follow-up of the cohort was 273 days (range 9-7013). Overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and cumulative incidence (CI) of relapse were calculated from DLI or second Allo-HCT date. In univariate analysis, second Allo-HCT was associated with higher OS (p = 0.021) and a trend to higher DFS (p = 0.097) and CI of relapse (p = 0.094) on univariate analysis. However, multivariate analysis showed comparable outcomes between DLI and second Allo-HCT, with the time interval to relapse before DLI or second Allo-HCT the only statistically significant factor with an impact on OS and DFS. Within the DLI cohort, T-cell-depleted Allo-HCT was associated with higher OS (p = 0.003) and DFS (p < 0.001) and lower CI of relapse (p = 0.002) than T-cell-replete Allo-HCT. Overall, in this cohort of AL patients, second Allo-HCT and DLI associated similar outcomes. As in other relapse studies, the length of remission (time to relapse) was identified as a factor with statistical impact on survival. Further studies are warranted., (Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)